[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

IL277071B1 - AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS - Google Patents

AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Info

Publication number
IL277071B1
IL277071B1 IL277071A IL27707120A IL277071B1 IL 277071 B1 IL277071 B1 IL 277071B1 IL 277071 A IL277071 A IL 277071A IL 27707120 A IL27707120 A IL 27707120A IL 277071 B1 IL277071 B1 IL 277071B1
Authority
IL
Israel
Prior art keywords
alkyl
cycloalkyl
independently selected
membered heterocycloalkyl
aryl
Prior art date
Application number
IL277071A
Other languages
Hebrew (he)
Other versions
IL277071A (en
IL277071B2 (en
Original Assignee
Incyte Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Incyte Corp filed Critical Incyte Corp
Publication of IL277071A publication Critical patent/IL277071A/en
Publication of IL277071B1 publication Critical patent/IL277071B1/en
Publication of IL277071B2 publication Critical patent/IL277071B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-γ INHIBITORS TECHNICAL FIELDThe present invention provides aminopyrazine diol compounds that modulate the activity of phosphoinositide 3-kinases-gamma (PI3Kγ) and are useful in the treatment of diseases related to the activity of PI3Kγ including, for example, autoimmune diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. BACKGROUNDThe phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipid signaling kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring (Cantley, Science, 2002, 296(5573):1655-7). PI3Ks are divided into three classes (class I, II, and III) according to their structure, regulation and substrate specificity. Class I PI3Ks, which include PI3K D , PI3K E , PI3K J , and PI3KGu000f are a family of dual specificity lipid and protein kinases that catalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate (PIP 2) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP 3). PIP 3 functions as a second messenger that controls a number of cellular processes, including growth, survival, adhesion and migration. All four class I PI3K isoforms exist as heterodimers composed of a catalytic subunit (p110) and a tightly associated regulatory subunit that controls their expression, activation, and subcellular localization. PI3K D , PI3K Eu000f and PI3K Gu0003 associate with a regulatory subunit known as p85 and are activated by growth factors and cytokines through a tyrosine kinase-dependent mechanism (Jimenez, et al., J Biol Chem., 2002, 277(44):41556-62) whereas PI3K Ju0003 associates with two regulatory subunits (p101 and p84) and its activation is driven by the activation of G-protein-coupled receptors (Brock, et al., J Cell Biol., 2003, 160(1):89-99). PI3K D and PI3K Eu0003 are ubiquitously expressed. In contrast, PI3K Ju0003 and PI3K Gu0003 are predominantly expressed in leukocytes (Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204). Expression of PI3K J is mainly restricted to hematopoietic system, although it can be also detected at lower level in endothelium, heart and brain. PI3K J knock-out or kinase dead knock in mice are normal and fertile and do not present any overt adverse phenotypes. Analysis at the cellular level indicates that PI3K J is required for GPCR ligand-induced PtdINs (3,4,5)P3 production, chemotaxis and respiratory burst in neutrophils. PI3K J -null macrophages and dendritic cell exhibit reduced migration towards various chemoattractants. T-cells deficient in PI3K J show impaired cytokine production in response to anti-CD3 or Con A stimulation. PI3K J working downstream of adenosine A3A receptor is critical for sustained Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) degranulation of mast cells induced by FC H RI cross-linking with IgE. PI3K J is also essential for survival of eosinophils (Ruckle et al., Nat. Rev. Drug Discovery, 2006, 5, 903-918) Given its unique expression pattern and cellular functions, the potential role of PI3K J in various autoimmune and inflammatory disease models has been investigated with genetic and pharmacological tools. In asthma and allergy models, PI3K J -/- mice or mice treated with PI3K J inhibitor showed a defective capacity to mount contact hypersensitivity and delayed-type hypersensitivity reactions. In these models, PI3K J was shown to be important for recruitment of neutrophils and eosinopohils to airways and degranulation of mast cells (see e.g. Laffargue et al., Immunity, 2002, 16, 441-451; Prete et al., The EMBO Journal, 2004, 23, 3505-3515; Pinho et al., L. Leukocyte Biology, 2005, 77, 800-810; Thomas et al., Eur. J. Immunol. 2005, 35, 1283-1291; Doukas et al., J. Pharmacol. Exp Ther. 2009, 328, 758-765). In two different acute pancreatitis models, genetic ablation of PI3K J significantly reduced the extent of acinar cell injury/necrosis and neutrophil infiltration without any impact on secretive function of isolated pancreatic acini (Lupia et al., Am. J. Pathology, 2004, 165, 2003-2011). PI3K J -/- mice were largely protected in four different models of rheumatoid arthritis (CIA, D -CII-IA, K/BxN serum transfer and TNF transgenic) and PI3K J inhibition suppressed the progression of joint inflammation and damage in the CIA and D -CII-IA models (see e.g., Camps et al., Nat. Medicine, 2005, 11, 939-943; Randis et al., Eur. J. Immunol, 2008, 38, 1215-1224; Hayer et al., FASB J., 2009, 4288-4298). In the MRL-lpr mouse model of human systemic lupus erythematous, inhibition of PI3K J reduced glomerulonephritis and prolonged life span (Barber et al., Nat. Medicine, 2005, 9, 933-935). There is evidence suggesting that chronic inflammation due to infiltration by myeloid-derived cells is a key component in the progression of neurodegeneration diseases, such as Alzheimer’s disease (AD) (Giri et al., Am. J. Physiol. Cell Physiol., 2005, 289, C264-C276; El Khoury et al., Nat. Med., 2007, 13, 432-438). In line with this suggestion, PI3K J inhibition was shown to attenuate A E (1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus and prevent the peptide-induced congnitive deficits and synaptic dysfunction in a mouse model of AD (Passos et al., Brain Behav. Immun. 2010, 24, 493-501). PI3K J deficiency or inhibition also was shown to delay onset and alleviate symptoms in experimental autoimmune encephalomyelitis in mice, a mouse model of human multiple sclerosis, which is another form of neurodegeneration disease (see e.g., Rodrigues et al., J. Neuroimmunol. 2010, 222, 90-94; Berod et al., Euro. J. Immunol. 2011, 41, 833-844; Comerford et al., PLOS one, 2012, 7, e45095; Li et al., Neuroscience, 2013, 253, 89-99). Chronic inflammation has been formally recognized as one of the hallmarks for many different types of cancers. Accordingly, selective anti-inflammatory drugs represent a novel 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) class of anti-cancer therapies (Hanahan and Weinberg, Cell, 2011, 144, 646-674). Since PI3K J is reported to mediate various inflammatory processes, its role as an immune oncology target has also been investigated. A recent study reported that PI3K J deficiency suppressed tumor growth in the syngeneic models of lung cancer, pancreatic cancer and melanoma (LLC, PAN02 and B16). PI3K J deficiency or inhibition also inhibited tumor growth in a spontaneous breast cancer model (Schmid et al., Cancer Cell, 2011, 19, 715-727). A further study reported that PI3K J deficiency could ameliorate inflammation and tumor growth in mice having colitis-associated colon cancer, (Gonzalez-Garcia et al., Gastroenterology, 2010, 138, 1373-1384). Detailed mechanistic analysis indicates that tumor infiltration by CD11b+ myeloid cells can cause protumorigenic inflammation at tumor sites and PI3K J in the myeloid cells is critical in mediating signaling of various chemoattractants in bring the cells to the tumor (Schmid et al., Cancer Cell, 2011, 19, 715-727). Other studies suggest that PI3K J is also required for differentiation of naïve myeloid cells into M2 macrophges at tumor sites. Mmacrophages promote tumor growth and progression by secreting immunosuppressive factors such arginase 1, which depletes the tumor microenvironment of arginine, thereby promoting T-cell death and NK cell inhibition (Schmidt et al., Cancer Res. 2012, 72 (Suppl 1: Abstract, 411; Kaneda et al., Cancer Res., 74 (Suppl 19: Abstact 3650)). In addition to its potential role in promoting protumorigenic microenvironment, PI3K J may play a direct role in cancer cells. PI3K J is reported to be required for signaling from the Kaposi’s sarcoma-associated herpevirus encoded vGPCR oncogene and tumor growth in a mouse model of sarcoma (Martin et al., Cancer Cell, 2011, 19, 805-813). PI3K J was also suggested to be required for growth of T-ALL (Subramanjam et al., Cancer Cell, 2012, 21, 459-472), PDAC and HCC cells (Falasca and Maffucci, Frontiers in Physiology, 2014, 5, 1-10). Moreover, in a survey of driver mutations in pancreatic cancer, PI3K J gene was found to contain second highest scoring predicted driven mutation (R839C) among the set of genes not previously identified as a driver in pancreatic cancer (Carter et al., Cancer Biol. Ther. 2010, 10, 582-587). Finally, PI3K J deficiency also has been reported to offer protection to experimental animals in different cardiovascular disease models. For examples, lack of PI3K J would reduce angiotension-evoked smooth muscle contraction and, therefore, protect mice from angiotension-induced hypertension (Vecchione et al., J. Exp. Med. 2005, 201, 1217-1228). In rigorous animal myocardial infarction models, PI3K J inhibition provided potent cardioprotection, reducing infarct development and preserving myocardial function (Doukas et al., Proc. Natl. Acad. Sci. USA, 2006, 103, 19866-19871).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) For these reasons, there is a need to develop new PI3Kγ inhibitors that can be used for the treatment of diseases such as cancer, autoimmune disorders, and inflammatory and cardiac diseases. This application is directed to this need and others. SUMMARYThe present invention relates to, inter alia, compounds of Formula (I): X N NH RR RRHOHO RR R (I) or pharmaceutically acceptable salts thereof, wherein constituent members are defined herein. The present invention further provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention further provides methods of inhibiting an activity of PI3Kγ kinase comprising contacting the kinase with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides methods of treating a disease or a disorder associated with abnormal PI3Kγ kinase expression or activity in a patient by administering to a patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present invention further provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. The present invention further provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. DETAILED DESCRIPTIONCompounds The present application provides, inter alia, compounds of Formula (I): X N NH RR RRHOHO RR R (I) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, Cy-C 1-6 alkyl-, CN, NO 2, ORa1, SRa1, NHORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)NRc1(ORa1), C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(=NRe1)Rb1, C(=NOH)Rb1, C(=NCN)Rb1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1C(=NOH)NRc1Rd1, NRc1C(=NCN)NRc1Rd1, NRc1C(=NRe1)Rb1, NRc1S(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O) 2Rb1, NRc1S(O)(=NRe1)Rb1, NRc1S(O) 2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O) 2Rb1, S(O) 2NRc1Rd1, OS(O)(=NRe1)Rb1, OS(O) 2Rb1, SF 5, P(O)Rf1Rg1, OP(O)(ORh1)(ORi1), P(O)(ORh1)(ORi1), and BRj1Rk1, wherein the C 1-6 alkyl, C 2-alkenyl, and C 2-6 alkynyl of R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; Cy is selected from C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; R, R and R are each independently selected from H, D, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NRcRd, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; R , R and R are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3, C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R, R, and R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein the C 1-6 haloalkyl of R, R, or R is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rc and Rd are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra1, Rb1, Rc1, and Rd1, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; each Re1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf1 and Rg1 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh1 and Ri1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj1 and Rk1 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj1 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra3, Rb3, Rc3, and Rd3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any Rc3 and Rd3, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; each Re3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)Rb4, C(=NCN)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, OS(O)(=NRe4)Rb4, OS(O) 2Rb4, SF 5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each RB is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O) 2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O) 2Rb2, S(O) 2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O) 2Rb2, SF 5, P(O)Rf2Rg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BRj2Rk2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Re2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf2 and Rg2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh2 and Ri2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj2 and Rk2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj2 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Re4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf4 and Rg4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh4 and Ri4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj4 and Rk4 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj4 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O) 2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O) 2Rc5, S(O) 2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O) 2Rb5, SF 5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RD are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RE substituents; 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra5, Rb5, Rc5, and Rd5 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RE substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RE substituents; each Re5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf5 and Rg5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh5 and Ri5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj5 and Rkis independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rjand Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RE is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O) 2Rb6, NRc6S(O) 2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O) 2Rb6, SF 5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of RE are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf6 and Rg6 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh6 and Ri6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj6 and Rk6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj6 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RG is independently selected from H, D, halo, CN, NO 2, SF 5, C 1-6 alkyl, C 1-alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl; and each RM is independently selected from H, D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-membered heterocycloalkyl)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-alkyl)aminocarbonylamino. In some embodiments: X is N or CR; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, Cy-C 1-6 alkyl-, CN, NO 2, ORa1, SRa1, NHORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)NRc1(ORa1), C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(=NRe1)Rb1, C(=NOH)Rb1, C(=NCN)Rb1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1C(=NOH)NRc1Rd1, NRc1C(=NCN)NRc1Rd1, NRc1C(=NRe1)Rb1, NRc1S(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O) 2Rb1, NRc1S(O)(=NRe1)Rb1, NRc1S(O) 2NRc1Rd1, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) S(O)Rb1, S(O)NRc1Rd1, S(O) 2Rb1, S(O) 2NRc1Rd1, OS(O)(=NRe1)Rb1, OS(O) 2Rb1, SF 5, P(O)Rf1Rg1, OP(O)(ORh1)(ORi1), P(O)(ORh1)(ORi1), and BRj1Rk1, wherein the C 1-6 alkyl, C 2-alkenyl, and C 2-6 alkynyl of R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; Cy is selected from C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; R, R and R are each independently selected from H, D, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NRcRd, wherein said C 1-6 alkyl can be optionally substituted by 1, 2, 3, 4, 5, or 6 D; R , R and R are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3, C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R, R, and R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein said C 1-6 haloalkyl of R, R, or R is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rc and Rd are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra1, Rb1, Rc1, and Rd1, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; each Re1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf1 and Rg1 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh1 and Ri1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj1 and Rk1 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj1 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra3, Rb3, Rc3, and Rd3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any Rc3 and Rd3, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; each Re3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)Rb4, C(=NCN)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, OS(O)(=NRe4)Rb4, OS(O) 2Rb4, SF 5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each RB is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O) 2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O) 2Rb2, S(O) 2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O) 2Rb2, SF 5, P(O)Rf2Rg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BRj2Rk2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Re2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Rf2 and Rg2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh2 and Ri2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj2 and Rk2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj2 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Re4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf4 and Rg4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh4 and Ri4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj4 and Rk4 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj4 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O) 2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O) 2Rc5, S(O) 2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O) 2Rb5, SF 5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra5, Rb5, Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Re5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf5 and Rg5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh5 and Ri5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj5 and Rkis independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rjand Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RE is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O) 2Rb6, NRc6S(O) 2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O) 2Rb6, SF 5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) membered heterocycloalkyl)-C 1-6 alkyl- of RE are each optionally substituted with 1, 2, 3, or independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf6 and Rg6 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh6 and Ri6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj6 and Rk6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj6 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RG is independently selected from H, D, halo, CN, NO 2, SF 5, C 1-6 alkyl, C 1-alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl; and each RM is independently selected from H, D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-membered heterocycloalkyl)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-alkyl)aminocarbonylamino. In some embodiments, X is N or CR; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, Cy-C 1-6 alkyl-, CN, NO 2, ORa1, SRa1, NHORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)NRc1(ORa1), C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, NRc1Rd1, NRc1NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, C(=NRe1)Rb1, C(=NOH)Rb1, C(=NCN)Rb1, C(=NRe1)NRc1Rd1, NRc1C(=NRe1)NRc1Rd1, NRc1C(=NOH)NRc1Rd1, NRc1C(=NCN)NRc1Rd1, NRc1C(=NRe1)Rb1, NRc1S(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O) 2Rb1, NRc1S(O)(=NRe1)Rb1, NRc1S(O) 2NRc1Rd1, S(O)Rb1, S(O)NRc1Rd1, S(O) 2Rb1, S(O) 2NRc1Rd1, OS(O)(=NRe1)Rb1, OS(O) 2Rb1, SF 5, P(O)Rf1Rg1, OP(O)(ORh1)(ORi1), P(O)(ORh1)(ORi1), and BRj1Rk1, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; Cy is selected from C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; R, R and R are each independently selected from H, D, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NRcRd, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-alkyl-, CN, NO 2, OH, COOH and NH 2; Rc and Rd are each independently selected from H and C 1-6 alkyl; each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra1, Rb1, Rc1, and Rd1, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; each Re1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf1 and Rg1 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh1 and Ri1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj1 and Rk1 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or any Rj1 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)Rb4, C(=NCN)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, OS(O)(=NRe4)Rb4, OS(O) 2Rb4, SF 5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl- C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each RB is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O) 2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O) 2Rb2, S(O) 2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O) 2Rb2, SF 5, P(O)Rf2Rg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BRj2Rk2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl- C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Re2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf2 and Rg2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh2 and Ri2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj2 and Rk2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj2 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Re4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf4 and Rg4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh4 and Ri4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj4 and Rk4 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj4 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) NRc5S(O) 2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O) 2Rc5, S(O) 2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O) 2Rb5, SF 5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1- 6 alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra5, Rb5, Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Re5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf5 and Rg5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh5 and Ri5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj5 and Rkis independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or any Rjand Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RE is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O) 2Rb6, NRc6S(O) 2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O) 2Rb6, SF 5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RE are each optionally substituted with 1, 2, 3, or independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf6 and Rg6 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh6 and Ri6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj6 and Rk6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj6 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RG is independently selected from H, D, halo, CN, NO 2, SF 5, C 1-6 alkyl, C 1-alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl; and each RM is independently selected from H, D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-membered heterocycloalkyl)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-alkyl)aminocarbonylamino.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, the compound of Formula (I) is a compound of Formula (II): N N NH RR RRHOHO RR R (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is a compound of Formula (III): N NH RR RRHOHO RR R R (III) or a pharmaceutically acceptable salt thereof. In some embodiments, R is H, D or C 1-6 alkyl. In some embodiments, R is H, D or methyl. In some embodiments, R is H. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, C(O)NRc1Rd1, C(O)ORa1, CN, NO 2, OH, COOH and NH 2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of R are each optionally substituted with 1, 2, 3, or independently selected RA substituents. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, Cy, Cy-C 1-6 alkyl-, C(O)NRc1Rd1, C(O)ORa1, CN, NO 2, OH, COOH and NH 2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1- 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 6 alkyl- of R are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R is selected from Cy, Cy-C 1-6 alkyl, C 1-6 haloalkyl, C(O)NRc1Rd1, and C(O)ORa1; and Cy is selected from C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, each of which are optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; In some embodiments, R is C(O)NRc1Rd1 or C(O)ORa1. In some embodiments, R is Cy, C(O)NRc1Rd1 or NRc1C(O)Rb1. In some embodiments, R is C(O)NRc1Rd1 or NRc1C(O)Rb1. In some embodiments, R is C(O)NRc1Rd1. In some embodiments, R is Cy. In some embodiments, R is C(O)NRc1Rd1 or NRc1C(O)Rb1, wherein Rc1 is H; and Rb1 and Rd1 are each independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1, wherein Rc1 is H; and Rd1 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1; and each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl- C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or independently selected RA substituents; and each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-alkynyl of RA is optionally substituted with 1, 2, or 3 independently selected RD substituents. In some embodiments, R is C(O)NRc1Rd1; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-alkynyl of RA is optionally substituted with 1, 2, or 3 independently selected RD substituents; each Ra4 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted CN, NO 2, or OH; and each RD is OH. In some embodiments, R is C(O)NRc1Rd1; and Rc1 is H; and Rd1 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1; and Rc1 is H; and Rd1 is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1; and Rc1 is H; and Rd1 is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R is C(O)NRc1Rd1; Rc1 is H; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) Rd1 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 4-membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl- of Rc1 and Rd1 are each optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents; and each RA is independently selected from oxo, C 1-6 alkyl, C 1-6 haloalkyl, CN, and ORa4, wherein the C 1-6 alkyl of RA is optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R is C(O)NRc1Rd1; Rc1 is H; Rd1 is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 are each optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; and each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, - CH 2OH, CN and OH. In some embodiments, R is C(O)NRc1Rd1; Rc1 is H; Rd1 is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 are each optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; and each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, -CH 2OH, CN and OH. In some embodiments, R is C(O)NRc1Rd1; Rc1 is H; and Rd1 is selected from 4-hydroxybicyclo[2.2.1]heptanyl and tetrahydropyranyl. In some embodiments, R is Cy, C(O)NRc1Rd1 or NRc1C(O)Rb1, wherein Rc1 is H; and Rb1 and Rd1 are each independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl-, each of which is optionally substituted by 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl- C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-alkyl-, of Ra1, Rb1, Rc1, and Rd1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; and each RA is independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino. In some embodiments, each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents. In some embodiments, Cy is a C 3-14 cycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a C 3-10 cycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a C 3-6 cycloalkyl optionally substituted with 1, 2, 3, or independently selected RA substituents. In some embodiments, Cy is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5-6 membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5 membered heteroaryl optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, Cy is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a 4-14 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents. In some embodiments, Cy is a 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is a 5 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected RA substituents. In some embodiments, Cy is selected from: , each of which is optionally substituted by 1 or 2 independently selected RA substituents. 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, R is selected from the following moieties: In some embodiments, Cy is selected from pyrazol-1-yl, pyrazol-4-yl, pyrazol-5-yl, isoxazol-5-yl, isothiazol-4-yl, isothizol-5-yl, oxazol-5-yl, thiazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, and 1,2,4-triazol-1-yl, each of which is substituted by 1 RA substituent. In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, C 1-haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1- 6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1- 6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, C 1-haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, and C 1-haloalkyl, wherein the C 1-6 alkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, C 1-haloalkyl, CN, ORa4, and NRc4Rd4; wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl,wherein the C 1-6 alkyl of Ra4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; and each RD is independently selected from D, OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, each RA is independently selected from methyl and CD 3. In some embodiments, each RA is methyl. In some embodiments, each RA is CD 3. In some embodiments, R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R is C 1-6 alkyl, which is optionally substituted by 1, 2, or independently selected RA groups. In some embodiments, R is C 1-6 alkyl. In some embodiments, R is propyl. In some embodiments, R is C 2-6 alkenyl, which is optionally substituted by 1, 2, or independently selected RA groups. In some embodiments, R is C 2-6 alkenyl. In some embodiments, R is propenyl or butenyl. In some embodiments, R is prop-1-enyl or but-1-enyl. In some embodiments, R is C 2-6 alkynyl, which is optionally substituted with 1, 2 or independently selected RA substituents. In some embodiments, R is ethynyl, propynyl, butynyl, or pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and pentynyl groups are each optionally substituted by 1, 2, or 3 independently selected RA groups. In some embodiments, R is selected from ethynyl, prop-1-ynyl, but-1-ynyl, and pent-1-ynyl, wherein the ethynyl is substituted by RA, and the prop-1-ynyl, but-1-ynyl, and pent-1-ynyl are each optionally substituted by 1, 2, or 3 independently selected RA groups. In some embodiments, R is selected from prop-1-ynyl, but-1-ynyl, and pent-1-ynyl, wherein the prop-1-ynyl, but-1-ynyl, and pent-1-ynyl are each optionally substituted by 1, 2, or 3 independently selected RA groups. In some embodiments, R is ethynyl, wherein the ethynyl is optionally substituted by 1, 2, or 3 independently selected RA groups. In some embodiments, each RA is independently selected from H, D, C 1-6 alkyl, C 1-haloalkyl, C 6-10 aryl, C 3-12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-12 cycloalkyl, 5-10 membered heteroaryl, and 4-12 membered heterocycloalkyl, are each optionally substituted with 1, 2, 3, 4, or 5 independently selected RD substituents. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, each RA is independently selected from H, D, C 1-6 alkyl, C 1-haloalkyl, C 6-10 aryl, C 3-12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-12 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-12 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 6-10 aryl, C 3-12 cycloalkyl, 5-10 membered heteroaryl, 4-12 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-12 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-12 membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected RD substituents, and wherein the connection of C 6-10 aryl-C 1-6 alkyl-, C 3-12 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl- and (4-12 membered heterocycloalkyl)-C 1-6 alkyl- groups to R (e.g., to an alkynyl group of R) may occur through the aforementioned ring or the C 1-6 alkyl group. In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, C 6-aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each Ra4 is independently selected from H and C 1-6 alkyl. In some embodiments, each RA is independently selected from D, halo, C 1-6 alkyl, C 6-aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or independently selected RD groups; and each Ra4 is independently selected from H and C 1-6 alkyl. In some embodiments, each RA is independently selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of RA are each optionally substituted by 1 or 2 independently selected RD groups. In some embodiments, each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, each Ra5 is independently selected from H and C 1-6 alkyl. In some embodiments, each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5; and each Ra5 is independently selected from H and C 1-6 alkyl. In some embodiments, each RA is independently selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; and each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5. In some embodiments, each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; and each RD is independently selected from methyl, cyano, cyanomethyl, and methoxy. In some embodiments, R is C 1-6 haloalkyl. In some embodiments, R is trifluoromethyl. In some embodiments, R is selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, each RA is independently selected from D, halo, oxo, C 1-alkyl, C 6-10 aryl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 5-membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4 and Rb4 are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with or 2 independently selected RD substituents. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, each RD is independently selected from OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and phenyl. In some embodiments, R is selected from C 3-12 cycloalkyl and 4-12 membered heterocycloalkyl, wherein the C 3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents; and each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O) 2Rb4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R is selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl of R are each optionally substituted with 1, 2, or 3 independently selected RA substituents; and each RA is independently selected from C 1-3 alkyl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O) 2Rb4, wherein the C 1-3 alkyl of RA are each optionally substituted with 1 or independently selected RD substituents. In some embodiments, R is selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O) 2Rb4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents; and each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or independently selected RD substituents. In some embodiments, R is selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or independently selected RD substituents; Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RD substituents; and each RD is independently selected from OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and phenyl. In some embodiments, R is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl of R are each optionally substituted with 1, 2, or independently selected RA substituents. In some embodiments, R is selected from azetidinyl and cyclobutyl, wherein the azetidinyl and cyclobutyl of R are each optionally substituted with 1, 2, or 3 independently selected RA substituents. In some embodiments, R is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl of R are each optionally substituted with 1, 2, or independently selected RA substituents; and each RA is independently selected from oxo, C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4 and S(O) 2Rb4, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl, of RA are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl of R are each optionally substituted with 1, 2, or independently selected RA substituents; each RA is independently selected from oxo, C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-alkyl, phenyl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl, of RA are each optionally substituted with 1 or 2 independently selected RD substituents; and Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the C 1-alkyl, C 3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents. In some embodiments, R is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl of R are each optionally substituted with 1, 2, or independently selected RA substituents; each RA is independently selected from C 1-3 alkyl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-3 alkyl of RA are each optionally substituted with 1 or independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the C 1-alkyl, C 3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RD substituents; and each RD is independently selected from OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, and phenyl. In some embodiments, R is selected from azetidinyl and cyclobutyl, wherein the azetidinyl and cyclobutyl of R are each optionally substituted with 1, 2, or 3 RA substituents independently selected from (1-methyl-1H-pyrazol-4-yl)sulfonyl, ethylcarboxylate, oxo, cyclopropyl, butyl, acetyl, cyclopropanecarbonyl, phenyl, methylphenyl, dimethylphenyl, pyrindinyl, thiazolyl, trifluoromethylphenyl, cyanophenyl, hydroxyphenyl, hydroxymethyl, cyanoethyl, oxohexahydropyrrolo[1,2-a]pyrazine-2-yl, furan-2-carbonyl, cyanopyrazinyl, and ethoxyphenyl. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, R is methyl or CD 3. In some embodiments, R is methyl. In some embodiments, R is CD 3. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is H, D or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is H, D or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R and R are each H. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, OH, COOH and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, CN, NO 2, OH, COOH and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is H, D or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is methyl. In some embodiments, R is CD 3. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is C 1-6 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Y is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl. In other embodiments, each Y is independently selected from halo and C 1-6 haloalkyl. In some embodiments, R is H, CH 2F, CHF 2 or CF 3. In some embodiments, R is selected from CF 3, CCl 3, CF 2H, CCl 2H, CF 2Y, CCl 2Y, CFH 2, CClH 2, CFHY, CClHY, CF(Y) 2 and CCl(Y) 2. In some embodiments, R is selected from CF 3, CF 2H, CF 2Y, CFH 2, CFHY, and CF(Y) 2. In some embodiments, R is C 1-6 haloalkyl, wherein each halogen is F. In some embodiments, R is C 1-6 haloalkyl, wherein each halogen is Cl. In some embodiments, R is selected from CH 2F, CHF 2, CF 3, and CF 2CF 3. In some embodiments, R is CH 2F, CHF 2, or CF 3. In some embodiments, R is CF 3. In some embodiments, R is CH 2F. In some embodiments, R is CHF 2. In some embodiments, R is CF 2CF 3. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, OH, COOH and NH 2. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, CN, NO 2, OH, COOH and NH 2. In some embodiments, R is H, D or C 1-6 alkyl. In some embodiments, R is methyl or ethyl. In some embodiments, R is CD 3. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, OH, COOH and NH 2, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, CN, NO 2, OH, COOH and NH 2, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, R is H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D. In some embodiments, R is methyl or ethyl. In some embodiments, R is CD 3. In some embodiments, R is H. In some embodiments, R is D. In some embodiments, Rand R are each H. In some embodiments, R and R, together with the C atom to which they are attached, form a cyclopropyl or cyclobutyl. In some embodiments, R and R, together with the C atom to which they are attached, form a cyclopropyl. In some embodiments, each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O) 2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O) 2Rc5, S(O) 2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O) 2Rb5, SF 5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents. In some embodiments, each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra5, Rb5, Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RE substituents. In some embodiments, each RE is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O) 2Rb6, NRc6S(O) 2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O) 2Rb6, SF 5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RE are each optionally substituted with 1, 2, 3, or independently selected RG substituents. In some embodiments, each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, or 4 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RG substituents. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, the compound is a compound of Formula (II): N N NH RR RRHOHO RR R (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (III): N NH RR RRHOHO RR R R (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (IV): (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of Formula (V): (V) 15 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or a pharmaceutically acceptable salt thereof. In some embodiments, X is N or CR; R is H, D or C 1-6 alkyl; R is Cy, C(O)NRc1Rd1 or NRc1C(O)Rb1; Cy is 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3- 7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1- 6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Rb1, Rc1, and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1- 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1- 6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is Cy. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is C(O)NRc1Rd1. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is NRc1C(O)Rb1. In some embodiments, X is N or CR; R is H, D or C 1-6 alkyl; R is Cy, C(O)NRc1Rd1 or NRc1C(O)Rb1; Cy is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Rb1, Rc1, and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is Cy. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is C(O)NRc1Rd1. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is NRc1C(O)Rb1. In some embodiments: X is N or CH; R is C(O)NRc1Rd1; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-alkynyl of RA is optionally substituted with 1, 2 or 3 independently selected RD substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra4 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by CN, NO 2, or OH; each RD is OH; each R, R and R is independently selected from H, D, halo, CN, OH, C 1-3 alkyl, and C 1-3 haloalkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R, R, and R is independently selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl. In some embodiments: X is N; R is C(O)NRc1Rd1; Rc1 is H; Rd1 is selected from ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 is optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, -CH 2OH, CN, and OH; R is selected from H, methyl, and CD 3. R and R are each H; R is selected from CH 2F, CHF 2, and CF 3; and R and R are each H. In some embodiments: X is N or CH; R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1, 2, or independently selected RA substituents; each RA is independently selected from D, halo, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; each Ra4 is independently selected from H and C 1-6 alkyl; each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5; each Ra5 is independently selected from H and C 1-6 alkyl; each R, R and R is independently selected from H, D, halo, CN, OH, C 1-3 alkyl, and C 1-3 haloalkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R, R, and R is independently selected from H, D, C 1-6 alkyl, and C 1-haloalkyl. In some embodiments: X is N or CH; R is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted with 1 or independently selected RA substituents; each RA is independently selected from D, halo, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2, and ORa4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; each Ra4 is independently selected from H and C 1-6 alkyl; each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5; each Ra5 is independently selected from H and C 1-6 alkyl; R is selected from H and C 1-6 alkyl; R is selected from H and C 1-6 alkyl; R is selected from H and C 1-6 alkyl; R is a C 1-3 haloalkyl, wherein each halogen of the C 1-3 haloalkyl is independently selected from F and Cl; and each R and R is independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments: X is N; R is selected from trifluoromethyl, propyl, propenyl, ethynyl, propynyl, butynyl, and pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) pentynyl groups are each optionally substituted by 1, 2, or 3 independently selected RA groups; each RA is independently selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, and ORa4, wherein the C 1-6 alkyl, C 6-aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; each Ra4 is independently selected from H and C 1-6 alkyl; each RD is independently selected from halo, C 1-6 alkyl, CN, cyano-C 1-6 alkyl, and ORa5; each Ra5 is independently selected from H and C 1-6 alkyl; R is C 1-6 alkyl; R is H; R is H; R is a C 1-3 haloalkyl, wherein each halogen of the C 1-3 haloalkyl is independently selected from F and Cl; R is H; and R is H. In some embodiments: X is N; R is selected from trifluoromethyl, propyl, propenyl, ethynyl, propynyl, butynyl, and pentynyl, wherein the ethynyl is optionally substituted by RA, and the propynyl, butynyl, and pentynyl groups are each optionally substituted by 1, 2, or 3 independently selected RA groups; each RA is independently selected from methyl, cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, imidazopyrazinyl, hydroxyl, and methoxy, wherein the cyclopropyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, and imidazopyrazinyl of RA are each optionally substituted by 1 or 2 independently selected RD groups; each RD is independently selected from methyl, cyano, cyanomethyl, and methoxy; R is C 1-6 alkyl; R is H; R is H; R is CHF 2 or CF 3; R is H; and R is H. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments: X is N or CH; R is selected from C 3-12 cycloalkyl and 4-12 membered heterocycloalkyl, wherein the C 3-12 cycloalkyl and 4-12 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-6 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 5-10 membered heteroaryl of RA are each optionally substituted with 1 or 2 independently selected RD substituents; each Ra4, Rb4, Rc4 and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-alkyl, phenyl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl of Ra4 and Rb4 are each optionally substituted with 1 or 2 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RD substituents; each R, R and R is independently selected from H, D, halo, CN, OH, C 1-3 alkyl, and C 1-3 haloalkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; and each R, R and R is independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments: X is N or CH; R is selected from C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 RA substituents; each RA is independently selected from C 1-3 alkyl, C(O)Rb4, C(O)ORa4, C(O)NRc4Rd4, and S(O) 2Rb4, wherein the C 1-3 alkyl of RA are each optionally substituted with 1 or independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl, wherein the C 1-alkyl, C 3-6 cycloalkyl, 5-7 membered heteroaryl, and 4-7 membered heterocycloalkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1 or 2 independently selected RD substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RD substituents; each RD is independently selected from OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and phenyl; R is selected from H, methyl and CD 3; R and R are each H; R is selected from CH 2F, CHF 2, and CF 3; and R and R are each H. In some embodiments: X is N; R is selected from azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl, wherein the azetidinyl, cyclobutyl, piperazinyl, and hexahydropyrrolo[1,2-a]pyrazinyl of R are each optionally substituted with 1, 2, or 3 RA substituents independently selected from (1-methyl-1H-pyrazol-4-yl)sulfonyl, ethylcarboxylate, oxo, cyclopropyl, butyl, acetyl, cyclopropanecarbonyl, phenyl, methylphenyl, dimethylphenyl, pyrindinyl, thiazolyl, trifluoromethylphenyl, cyanophenyl, hydroxyphenyl, hydroxymethyl, cyanoethyl, oxohexahydropyrrolo[1,2-a]pyrazine-2-yl, furan-2-carbonyl, cyanopyrazinyl, and ethoxyphenyl; R is selected from H, methyl and CD 3; R and R are each H; R is selected from CH 2F, CHF 2, and CF 3; and R and R are each H. In some embodiments, X is N or CR; R is H; R is Cy, C(O)NRc1Rd1 or NRc1C(O)Rb1; Cy is 5-membered heteroaryl, which is optionally substituted with 1, 2, or independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Rb1, Rc1, and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Rb1, Rc1, and Rd1 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is Cy. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is C(O)NRc1Rd1. In some embodiments, groups X, R, Rb1, Rc1, Rd1, Cy, RA, R, R, R, R, R, R, Ra4, Rb4, Rc4, Rd4, and RD are as defined above, and R is NRc1C(O)Rb1. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: X is N or CR; R is H, D or C 1-6 alkyl; Cy is 5-14 membered heteroaryl, which is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1- 6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1- 6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: X is N or CR; R is H, D or C 1-6 alkyl; Cy is 5-6 membered heteroaryl, which is optionally substituted with 1, 2, 3, or independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: X is N or CR; R is H; Cy is 5-membered heteroaryl, which is optionally substituted with 1, 2, or independently selected RA substituents; R, R, and R are each independently selected from H, D, halo, C 1-6 alkyl, C 1-alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) R, R and R are each independently selected from H, D, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from 5 membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; R is C 1-6 alkyl, which is optionally substituted with 1, 2, or 3 D; R and R are each independently H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; R is H, D, C 1-6 alkyl or C 1-6 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R and R are each independently H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, and OS(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, and C 1-haloalkyl, wherein the C 1-6 alkyl of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino. In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from 5 membered heteroaryl, which is optionally substituted with 1, 2, or 3 independently selected RA substituents; R is C 1-6 alkyl, which is optionally substituted with 1, 2, or 3 D; R and R are each independently H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; R is H, D, C 1-6 alkyl or C 1-6 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; R and R are each independently H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, ORa4, and NRc4Rd4; wherein the C 1-6 alkyl of RA are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; each Ra4, Rc4, and Rd4 is independently selected from H, D, C 1-6 alkyl, and C 1-haloalkyl, wherein the C 1-6 alkyl of Ra4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, or 4 independently selected RD substituents; and each RD is independently selected from D, OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, the compound is a compound of Formula (V): (V) or a pharmaceutically acceptable salt thereof, wherein: Cy is selected from: , each of which is optionally substituted by 1 or 2 independently selected RA substituents; R is methyl or CD 3; R and R are each H; R is C 1-6 haloalkyl, wherein each halogen is F; R and R are each H; and each RA is methyl or CD 3. In some embodiments, the compound is compound of Formula (VI), (VIb), or (VIc): (VI), N N NHR RHOHO NO Rc1Rd1 R R (VIb), N N NHR RHOHO RAR R (VIc), Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound of Formula (VII), (VIIb), or (VIIc): (VII) N N NHR RHOHO NO Rc1Rd1 (VIIb), N N NHR RHOHO RA (VIIc), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound of Formula (VIII), (VIIIb), or (VIIIc): (VIII), N N NHR CFHOHO NO Rc1Rd1 (VIIIb), Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) N N NHR CFHOHO RA (VIIIc), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from: 2-(3-(5-Amino-6-(1-(methyl-d 3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(isothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(1H-1,2,3-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; (2-(3-(5-Amino-6-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; 2-(3-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2-diol; 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-(4- hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide; 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 2-(3-(5-amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol; 2-(3-(5-amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol; 3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxy-3-methylbutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 2-(3-(5-amino-6-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)azetidin-3-yl)pyrazin-2-yl)- 4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; (3-(3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)cyclobutyl)(3-hydroxyazetidin-1-yl)methanone; 3-amino-N-((1s,3R)-3-cyanocyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1S,2S)-2-hydroxycyclohexyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((trans)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1s,3R)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-6-(2-(methyl-d 3)-5- ((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1s,3R)-3-hydroxy-1-methylcyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((S)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) (S)-3-amino-N-(2-cyano-2-methylpropyl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((R)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3- dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1S,2S)-2-hydroxycyclohexyl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxamide; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-N- (tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-((S)-1-hydroxypropan-2-yl)pyrazine-2-carboxamide; 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide; (3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazin-2-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N- isopropylpyrazine-2-carboxamide; 3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(3-methyltetrahydrofuran-3-yl)pyrazine-2-carboxamide; and 2-(3-(5-amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol; or an enationmer, diastereomer or tautomer thereof; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the (S)-enantiomer of one of the preceding compounds, or a pharmaceutically acceptable salt 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) thereof. In some embodiments, the compound is the (R)-enantiomer of one of the preceding compounds, or a pharmaceutically acceptable salt thereof. In some embodiments, the invention includes all stereoisomers of the aforementioned compounds. In some embodiments, the compound is a compound of Formula (I): X N NH RR RRHOHO RR R (I) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2; R is selected from C(O)NRc1Rd1; R, R and R are each independently selected from H, D, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NRcRd, wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, or 6 D; R, R and R are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), C(O)ORa3, C(=NRe3)Rb3, C(=NOH)Rb3, C(=NCN)Rb3, and C(=NRe3)NRc3Rd3, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R, R, and R are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; and wherein the C 1-6 haloalkyl of R, R, or R is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) or R and R substituents, together with the ring atoms to which they are attached, form a C 3-10 cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected RB substituents; Rc and Rd are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc and Rd, are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or independently selected RA substituents; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra3, Rb3, Rc3, and Rd3 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; or, any Rc3 and Rd3, attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RB substituents; each Re3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, C(=NRe4)Rb4, C(=NOH)Rb4, C(=NCN)Rb4, C(=NRe4)NRc4Rd4, NRc4C(=NRe4)NRc4Rd4, NRc4C(=NRe4)Rb4, NRc4C(=NOH)NRc4Rd4, NRc4C(=NCN)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)NRc4Rd4, NRc4S(O) 2Rb4, NRc4S(O) 2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O) 2Rb4, S(O) 2NRc4Rd4, OS(O)(=NRe4)Rb4, OS(O) 2Rb4, SF 5, P(O)Rf4Rg4, OP(O)(ORh4)(ORi4), P(O)(ORh4)(ORi4), and BRj4Rk4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1- 6 alkyl- of RA is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each RB is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, C(=NRe2)Rb2, C(=NOH)Rb2, C(=NCN)Rb2, C(=NRe2)NRc2Rd2, NRc2C(=NRe2)NRc2Rd2, NRc2C(=NRe2)Rb2, NRc2C(=NOH)NRc2Rd2, NRc2C(=NCN)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)NRc2Rd2, NRc2S(O) 2Rb2, NRc2S(O) 2NRc2Rd2, S(O)Rb2, S(O)NRc2Rd2, S(O) 2Rb2, S(O) 2NRc2Rd2, OS(O)(=NRe2)Rb2, OS(O) 2Rb2, SF 5, P(O)Rf2Rg2, OP(O)(ORh2)(ORi2), P(O)(ORh2)(ORi2), and BRj2Rk2, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1- 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 6 alkyl- of RB is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra2, Rb2, Rc2, and Rd2 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RM substituents; each Re2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf2 and Rg2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh2 and Ri2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj2 and Rk2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj2 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; or, any Rc4 and Rd4 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RD substituents; each Re4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf4 and Rg4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh4 and Ri4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj4 and Rk4 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj4 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, C(=NRe5)Rb5, C(=NOH)Rb5, C(=NCN)Rb5, C(=NRe5)NRc5Rd5, NRc5C(=NRe5)NRc5Rd5, NRc5C(=NRe5)Rb5, NRc5C(=NOH)NRc5Rd5, NRc5C(=NCN)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)NRc5Rd5, NRc5S(O) 2Rb5, NRc5S(O) 2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O) 2Rc5, S(O) 2NRc5Rd5, OS(O)(=NRe5)Rb5, OS(O) 2Rb5, SF 5, P(O)Rf5Rg5, OP(O)(ORh5)(ORi5), P(O)(ORh5)(ORi5), and BRj5Rk5, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1- 6 alkyl- of RD are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra5, Rb5, Rc5, and Rd5 are each optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; or, any Rc5 and Rd5 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected RE substituents; each Re5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf5 and Rg5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) each Rh5 and Ri5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj5 and Rkis independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rjand Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RE is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa6, SRa6, NHORa6, C(O)Rb6, C(O)NRc6Rd6, C(O)NRc6(ORb6), C(O)ORa6, OC(O)Rb6, OC(O)NRc6Rd6, NRc6Rd6, NRc6NRc6Rd6, NRc6C(O)Rb6, NRc6C(O)ORa6, NRc6C(O)NRc6Rd6, C(=NRe6)Rb6, C(=NOH)Rb6, C(=NCN)Rb6, C(=NRe6)NRc6Rd6, NRc6C(=NRe6)NRc6Rd6, NRc6C(=NRe6)Rb6, NRc6C(=NOH)NRc6Rd6, NRc6C(=NCN)NRc6Rd6, NRc6S(O)Rb6, NRc6S(O)NRc6Rd6, NRc6S(O) 2Rb6, NRc6S(O) 2NRc6Rd6, S(O)Rb6, S(O)NRc6Rd6, S(O) 2Rc6, S(O) 2NRc6Rd6, OS(O)(=NRe6)Rb6, OS(O) 2Rb6, SF 5, P(O)Rf6Rg6, OP(O)(ORh6)(ORi6), P(O)(ORh6)(ORi6), and BRj6Rk6, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-membered heterocycloalkyl)-C 1-6 alkyl- of RE are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Ra6, Rb6, Rc6, and Rd6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra6, Rb6, Rc6, and Rd6 are each optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; or, any Rc6 and Rd6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-, 5-, 6-, or 7-membered 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected RG substituents; each Re6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rf6 and Rg6 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rh6 and Ri6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered hetereocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered hetereocycloalkyl)-C 1-6 alkyl-; each Rj6 and Rk6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or any Rj6 and Rkattached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl; each RG is independently selected from H, D, halo, CN, NO 2, SF 5, C 1-6 alkyl, C 1-alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl; and each RM is independently selected from H, D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-membered heterocycloalkyl)-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, C 1-alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-alkyl)aminocarbonylamino. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. At various places in the present specification, divalent linking substituents are described. It is specifically intended that each divalent linking substituent include both the forward and backward forms of the linking substituent. For example, -NR(CR’R’’) n- includes both -NR(CR’R’’) n- and -(CR’R’’) nNR-. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. The term "n-membered" where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. As used herein, the phrase "each ‘variable’ is independently selected from" means substantially the same as wherein "at each occurrence ‘variable’ is selected from." Throughout the definitions, the term "C n-m" indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-3, C 1-4, C 1-6, and the like. As used herein, the term "C n-m alkyl", employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, "C n-m alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, "C n-m alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term "C n-m alkoxy", employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "amino" refers to a group of formula –NH 2. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "C n-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 5 to 14 carbon atoms. In some embodiments, the aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl is phenyl. As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl. As used herein, "C n-m haloalkoxy" refers to a group of formula –O-haloalkyl having n to m carbon atoms. Example haloalkoxy groups include OCF 3 and OCHF 2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m haloalkyl", employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to carbon atoms. Example haloalkyl groups include CF 3, C 2F 5, CHF 2, CH 2F, CCl 3, CHCl 2, C 2Cl 5 and the like.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) As used herein, the term "C n-m alkylamino" refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylcarbonyl" refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkoxycarbonylamino" refers to a group of formula -NHC(O)O(C n-m alkyl), wherein the alkyl group has n to m carbon atom. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylsulfonylamino" refers to a group of formula -NHS(O) 2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "aminosulfonyl" refers to a group of formula -S(O) 2NH 2. As used herein, the term "C n-m alkylaminosulfonyl" refers to a group of formula -S(O) 2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "di(C n-m alkyl)aminosulfonyl" refers to a group of formula -S(O) 2N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "aminosulfonylamino" refers to a group of formula -NHS(O) 2NH 2. As used herein, the term "C n-m alkylaminosulfonylamino" refers to a group of formula -NHS(O) 2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "di(C n-m alkyl)aminosulfonylamino" refers to a group of formula -NHS(O) 2N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to carbon atoms. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) As used herein, the term "aminocarbonylamino", employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH 2. As used herein, the term "C n-m alkylaminocarbonylamino" refers to a group of formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "di(C n-m alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl) 2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylcarbamyl" refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "thio" refers to a group of formula -SH. As used herein, the term "C n-m alkylthio" refers to a group of formula -S-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylsulfinyl" refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "C n-m alkylsulfonyl" refers to a group of formula -S(O) 2- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "carbamyl" to a group of formula –C(O)NH 2. As used herein, the term "carbonyl", employed alone or in combination with other terms, refers to a -C(O)- group. As used herein, the term "cyano-C 1-6 alkyl" refers to a group of formula -(C 1-alkylene)-CN. As used herein, the term "HO-C 1-6 alkyl" refers to a group of formula -(C 1-6 alkylene)-OH. As used herein, the term "HO-C 1-3 alkyl" refers to a group of formula -(C 1-3 alkylene)- OH. As used herein, the term "C 1-6 alkoxy-C 1-6 alkyl" refers to a group of formula -(C 1-alkylene)-O(C 1-3 alkyl). As used herein, the term "C 1-6 alkoxy-C 1-3 alkyl" refers to a group of formula -(C 1-alkylene)-O(C 1-3 alkyl). 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) As used herein, the term "carboxy" refers to a group of formula -C(O)OH. As used herein, the term "di(C n-m-alkyl)amino" refers to a group of formula -N(alkyl) 2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "di(C n-m-alkyl)carbamyl" refers to a group of formula – C(O)N(alkyl) 2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term "aminocarbonyloxy" refers to a group of formula -OC(O)NH 2. As used herein, the term "C 1-3 alkylcarbonyloxy" refers to a group of formula - OC(O)(C 1-3 alkyl). As used herein, the term "C 1-3 alkylaminocarbonyloxy" refers to a group of formula -OC(O)NH(C 1-3 alkyl). As used herein, the term "di(C 1-3 alkyl)aminocarbonyloxy" refers to a group of formula -OC(O)N(C 1-3 alkyl) 2, wherein the two alkyl groups each has, independently, 1 to 3 carbon atoms. As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused rings) groups, spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring-forming carbons (i.e., C 3-14). In some embodiments, the cycloalkyl is a C 3-14 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, and Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S and B, wherein any ring forming N is optionally an N-oxide group. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B. In some embodiments, the heteroaryl is a 5-14 membered monocyclic, bicyclic heteroaryl, or tricyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S and B. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine, thieno[3,2-b]pyridine, imidazo[1,2- a]pyridine, 1,5-naphthyridine, 1H-pyrazolo[4,3-b]pyridine and the like. A five-membered heteroaryl is a heteroaryl group having five ring-forming atoms wherein one or more (e.g., 1, 2, or 3) of the ring-forming atoms are independently selected from N, O, S or B. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine. A six-membered heteroaryl is a heteroaryl group with a ring having six ring-forming atoms wherein one or more (e.g., 1, 2, or 3) of the ring-forming atoms are independently Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) selected from N, O, S and B. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, "heterocycloalkyl" refers to monocyclic or polycyclic heterocycles having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms is replaced by a heteroatom selected from N, O, S and B, and wherein the ring-forming carbon atoms and heteroatoms can be optionally substituted by one or more oxo or sulfide (e.g., C(O), S(O), C(S), or S(O) 2, etc.). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-14- or 4-14- or 3-12- or 4-12-, or 3-10-, or 4-10- or 3-7- or 4-7- or 5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-14 membered bridged biheterocycloalkyl ring optionally substituted with 0 to 2 additional heteroatoms independently selected from N, O, S and B). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic heterocyclic ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring- forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S and B and having one or more oxidized ring members. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline, azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl, diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl, azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl, oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl, oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl, azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl, azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl, oxa-diazaspiro[4.4]nonanyl and the like. As used herein, "C o-p cycloalkyl-C n-m alkyl-" refers to a group of formula cycloalkyl- alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. As used herein "C o-p aryl-C n-m alkyl-" refers to a group of formula aryl-alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms. As used herein, "heteroaryl-C n-m alkyl-" refers to a group of formula heteroaryl-alkylene-, wherein alkylene linking group has n to m carbon atoms. As used herein "heterocycloalkyl-C n-m alkyl-" refers to a group of formula heterocycloalkyl-alkylene-, wherein alkylene linking group has n to m carbon atoms. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position. As used herein, the term "oxo" refers to an oxygen atom (i.e., =O) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O or C(O)), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl or sulfonyl group. As used herein, the term "independently selected from" means that each occurrence of a variable or substituent, e.g., RM or RA, are independently selected at each occurrence from the applicable list. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R)-configuration. In some embodiments, the compound has the (S)-configuration. The Formulas (e.g., Formula (I), etc.) provided herein include stereoisomers of the compounds. Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art. The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The present application also includes pharmaceutically acceptable salts of the compounds described herein. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso- 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) propanol, or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Synthesis As will be appreciated by those skilled in the art, the compounds provided herein, including salts and stereoisomers thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. Compounds of Formula (I) can be prepared as shown in Scheme 1 . Suitable starting materials 1-1 , where Y and Y are independently a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be converted to an appropriate substituted metal 1-2 (e.g., M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), or bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and a base, such as potassium acetate) and then coupled to 1-3 where Y is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)) to give to give compound 1-4 . Intermediate 1-4 can be converted to diol-containing intermediate 1-5 by exposure to reagents for dihydroxylation (e.g., osmium tetroxide and a re-oxidant such as N-methylmorpholine-N-oxide, or AD-mix α or AD-mix E ). Intermediate 1-5can be converted to an appropriate substituted metal 1-6 (e.g., M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, or Zn) under standard conditions (e.g., in the presence of a diboron reagent such as bis(pinacolato)diboron, a palladium catalyst, such as dichlorobis(triphenylphosphine)palladium(II), bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, or Pd 2(dba) 3 and a ligand (such as 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl) and a base, such as potassium acetate) and then coupled to 1-7 where Y and Y are independently a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) under 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)) to give to give compound 1-8 . Intermediate 1-8 can be converted to compounds of Formula (I) by cross-coupling with an appropriate metal R-M (where M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (II)). Alternatively, compounds of Formula (I) can be prepared from intermediate 1-8 by reacting with a nucleophile under SNAr conditions (e.g., by heating in the presence of a carbonate base, such as Cs 2CO 3). One skilled in the art would recognize that compounds of Formula (I) can also be prepared by reversing the order of the last two steps of Scheme 1 . Beginning with a suitably substituted intermediate 1-7 , where Y and Y are independently a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), coupling to install R can be perfomed before coupling with intermediate 1-6 , to afford compounds of Formula (I) .
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) Scheme 1.
RY YRY MRY R RR RY R RRHOHORRRR RM R RRHOHORRR RRHOHOR NX NHY RR RRHOHOR NX NHR dihydroxylation metalation metalationSuzuki, Stilleor Negishior R-HSNAr R-MY NX NHY YR RR Formula I 1-1 1 -2 1-3 1-4 1 -5 1-6 1-7 1-8 Suzuki, Stilleor Negishi Suzuki, Stilleor Negishi RRRR RRR Compounds of Formula (I) can be prepared as shown in Scheme 2 . Beginning with an appropriately substituted 1,4-dibromobenzene 2-1 , sequential reaction with strong base (e.g., nBuLi) at low temperature (e.g., -oC), followed by reaction with a carboxylic acid derivative RC(O)-L, such as an ester (methyl or ethyl ester) (e.g., methyl trifluoroacetate or ethyl trifluoroacetate) or a Weinreb amide (e.g., 2,2-difluoro-N-methoxy-N-methylacetamide), followed by in situ treatment with a second equivalent of strong base (e.g., nBuLi) at low temperature (e.g., -oC), followed by a second electrophile R-L (wherein L is a suitable leaving group (e.g., halogen, such as Cl, Br or I or a mesylate or tosylate)) affords ketone intermediate 2-2 . It will be appreciated by one skilled in the art that the order of the two steps can be reversed and the two steps can also be performed separately, stepwise. Intermediate 2-2 can be halogenated by exposure to halogenating conditions to introduce Y (e.g., bromine in the presence of AlCl 3 and mild heating), or N-halo-succinimide (e.g., N-bromosuccinimide) and sulfuric acid in acetic acid at elevated temperature (e.g., oC)) to afford intermediate 2-3 . Intermediate 2-3 can be olefinated to afford intermediate 2-5 under standard conditions for olefination (e.g., Wittig conditions with an ylide such as 2-4 , where Y can be a phenyl, generated by reacting a phosphonium salt with a strong base (e.g., n-BuLi, potassium tert-butoxide or NaHMDS) or generated by a method similar to that found in Organic Letters, Vol.4, No. 10, 1671-1674, 2002 (e.g., in situ generation of methylenetriphenylphosphorane from the rhodium(I)-catalyzed decomposition of trimethylsilyldiazomethane in the presence of triphenylphosphine and 2-propanol)).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) Intermediate olefin 2-5 can be converted to compounds of Formula (I) by the methods outlined in Scheme 1 . Scheme 2.
Compounds of Formula (I) can also be prepared as shown in Scheme 3 . Appropriate starting materials 3-1 , where Y is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be coupled with an appropriately substituted metal R-M (where M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, Zn or ZnX (where X is a halogen such as iodide)) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II) optionally in the presence of an additive such as copper(I)iodide) to afford intermediate 3-2 . Intermediate 3-2 can then be halogenated by reaction with a reagent suitable for introducing the halogen Y (e.g., N-halosuccinimide such as N-iodosuccinimide, N-bromosuccinimide or N-chlorosuccinimide). Intermediate 3-3 bearing a suitable halogen Y (e.g., Cl, Br or I) can be elaborated to provide compounds of Formula (I)as shown in Scheme 1.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) Scheme 3.
Compounds of Formula (I) wherein R is an amide or a heterocycle can also be prepared as shown in Scheme 4 . The group Y of halo-substituted intermediate 4-1 (wherein Y is Cl, Br or I) can be converted to a nitrile group via nucleophilic displacement with a cyanide source (e.g., heating in the presence of NaCN) or by coupling with a cyanide source under standard Negishi conditions (e.g., heating with Zn(CN) 2 in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)) to afford intermediate 4-2 . The nitrile substituent of intermediate 4-2 can be converted to heterocycle-substituted compounds of Formula (I) by methods known to one skilled in the art (e.g., heating an appropriately substituted acyl hydrazide in the presence of an alkoxide base in an alcoholic solvent (e.g., NaOMe in MeOH or NaOEt in EtOH) to form a triazole; heating with an azide source such as NaN 3 to form a tetrazole). Nitrile containing intermediates 4-2 can also be converted to amide intermediates 4-4 (compounds of Formula (I) wherein R is an amide group) by hydrolysis (e.g., heating in the presence of aqueous acid; or with KOH in tBuOH) followed by coupling of the resulting acid with Rc1Rd1NH using standard amide coupling conditions (e.g., HATU). The group Y of halo-substituted intermediate 4-1 (wherein Y is Cl, Br or I) can be converted to an ester intermediate 4-3 under standard conditions for carbonylation (e.g., in the presence of a palladium catalyst, such as [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide, and an alcohol Ra1OH such as methanol or ethanol). Ester 4-3 can be converted to amide 4-4 (compounds of Formula (I) wherein R is an amide group) using amination conditions (e.g., by reacting with an amine such as Rc1Rd1NH in the presence of AlMe 3). Alternatively, ester 4-3 can be converted to amide 4-4 under standard conditions for hydrolysis, such as exposure to hydroxide base (e.g., LiOH, NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH) to furnish a carboxylic acid, followed by coupling of the resulting acid with Rc1Rd1NH using standard amide coupling conditions (e.g., HATU). Alternatively, the group Y of halo-substituted intermediate 4-1 can be converted directly to an amide 4-4 under standard conditions for carbonylation (e.g., in the presence of a palladium catalyst, such as [1,1'- 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) bis(diphenylphosphino)ferrocene]dichloropalladium, carbon monoxide, and an amine Rc1Rd1NH). Suitable amides 4-4 can be converted to compounds of Formula (I) wherein R is a heterocycle by methods known to one skilled in the art (e.g., when amide 4-4 is a hydrazide, it may be reacted with N-(triphenylphosphoranylidene)isocyanamide or with p-toluenesulfonic acid and an orthoester (e.g., triethylorthoformate) to form an 1,3,4- oxadiazole; an appropriately substituted amide can be reacted with an α-halocarbonyl compound (e.g., chloracetaldehyde) to afford an oxazole; an appropriately substituted amide can be reacted with 1,1-dimethoxy-N,N-dimethylmethanamine and hydroxylamine to form an 1,2,4-oxadiazole; conversion of the amide to a thioamide (e.g., using P 2S 5 or Lawesson’s reagent) before subjecting to the aforementioned reagents, would result in the corresponding thiadiazoles or thiazoles rather than oxadiazoles and oxazoles). Scheme 4.
As shown in Scheme 5 , the steps of Scheme 4 can be performed on appropriate starting materials 5-1 prior to coupling with intermediate 1-6 from Scheme 1 . This also affords intermediates useful in the preparation of compounds of Formula (I) wherein R is an amide or a heterocycle. Carboxylic acid intermediate 5-4 (e.g., Ra1=H and Y=an appropriate halogen such as Cl, Br or I) can be converted to amide intermediate 5-5 by reacting with an Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) amine (Rc1Rd1NH) under standard conditions for amide formation (e.g., using a coupling reagent such as HATU, in the presence of a base, such as diisopropylethylamine). Scheme 5.
Y NX NHY Y NX NH - 1 N Y NX NHRcyanation - 2 5 - 3 Y NX NH carbonylation OORa1 Y NX NHNORc1Rd1 HNRc1Rd1amide formation - 4 heterocycleformation heterocycleformation amide formation - 5 Sc he m e 1 For m ul a I RR RRHOHOR NX NHR RM R RRHOHOR 1- 6 R R Sc he m e 1 RM R RRHOHOR 1- 6 R Compounds of Formula (I) can be prepared as shown in Scheme 6 . Suitable starting materials 6-1 , wherein Yand Y are suitable halogen atoms (e.g., Cl, Br, or I) or pseudohalogens (e.g., OTf or OMs), can be converted to intermediate 6-3 by coupling with an organozinc species formed from a suitable optionally protected halide 6-2wherein Y is a halogen (e.g., Cl, Br, or I) under standard Negishi conditions (e.g., in the presence of Zn (which can be activated by agents such as 1,2-dibromoethane and TMSCl) and in the presence of a suitable palladium catalyst, (e.g., dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct and copper (I)iodide)). Intermediate 6-3 wherein Y is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) can be coupled with an appropriately substituted metal 6-4 (e.g., M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and a base (e.g., a carbonate base such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to give compounds 6-5 , which Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) themselves may be compounds of Formula (I) , or if protected (with a protecting group P, e.g., Boc), may be deprotected to afford compounds 6-6 using conditions suitable for removal of the protecting group which are also suitable in terms of compatibility with other functional groups that may be present in the molecule. Intermediates 6-6 may optionally be reacted with an electrophile RA-L (wherein L is a leaving group (e.g., halogen, such as Cl, Br or I or a mesylate or tosylate), or RA-L may be a carboxylic acid activated by exposure to a coupling reagent (e.g., DCC, EDC or HATU)) in the presence of a base (e.g., diisopropylethylamine or triethylamine) to furnish compounds of Formula (I) . Scheme 6.
Suzuki, Stilleor NegishiY NX NHY Fo r mula ( I) RRM RHORHORR RR NX NH 6- 1 N YnP Y NX NHNPn NegishiZn 6- 3 NP deprotect 6- 2 6- 5 R-L 6- 4 R 6- 6 nm RHOHO RR R RR NX NHHN nm RHOHO RR R RR NX NHNRAnm RHOHO RR mm Compounds of Formula (I) can be prepared as shown in Scheme 7 . Suitable starting materials 7-1 , wherein Y is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be converted to intermediates 7-3 by coupling with an appropriately substituted metal 7-2 (e.g., M is B(OH) 2, Bpin, BF 3K, Sn(Bu) 3, or Zn) under standard Suzuki conditions (e.g., in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and a base (e.g., a carbonate base, such as sodium carbonate or potassium carbonate)) or standard Stille conditions (e.g., in the presence of a palladium(0) catalyst, such as Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) tetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions (e.g., in the presence of a palladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)). Halogen-containing intermediate 7- 4 can be prepared by reacting intermediate 7-3 with a reagent suitable for introducing the halogen Y (e.g., N-halosuccinimide such as N-iodosuccinimide, N-bromosuccinimide or N- chlorosuccinimide). Intermediate 7-4 bearing a suitable halogen Y (e.g., Cl, Br or I) can be coupled with an organozinc derived from a suitable starting material 7-5 wherein Y is a suitable halogen (e.g., Br or I) under standard Negishi conditions (e.g., in the presence of Zn (which can be activated by agents such as 1,2-dibromoethane and TMSCl) and in the presence of a suitable palladium catalyst, (e.g., [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride)) to furnish compounds of Formula (I) . Scheme 7.
Suzuki, Stilleor NegishiY NX NH Fo r mula ( I) MR R R RHORHOR RR R NX NH 7- 1 YmnRA NegishiZn 7- 5 7- 3 7- 2 7- 4 halogenationRHOHO RR RR R NX NH RHOHO RR Y RR R NX NH RHOHO RR RAnm Compounds of Formula (I) can be prepared as shown in Scheme 8 . Intermediates 8- 1 which contain an ester (e.g., R is methyl or ethyl) can be hydrolyzed by exposure to 15 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) hydroxide base (e.g., LiOH, NaOH, KOH in water and a cosolvent such as THF, MeOH or EtOH) to furnish carboxylic acid intermediates 8-2 . Carboxylic acid containing intermediates can be coupled with an amine 8-3 in the presence of an amide coupling reagent (e.g., DCC, EDC and HATU) and in the presence of a suitable base (e.g., diisopropylethylamine or triethylamine) to furnish compounds of Formula (I) . Alternatively, ester containing intermediates can be converted directly to amide-containing compounds of Formula (I) by reaction at elevated temperature (e.g., oC) with an amine 8-3 in the presence of a Lewis acid catalyst (e.g., AlMe 3). Scheme 8.
Fo r m ul a ( I ) HNR''R' 8- 2 8- 3 8- 1 8- 3 hydrolysiscoupling Lewis acid R RR NX NHOO RHORHOR mn R R RR NX NHOO RHORHOR mn R R RR NX NHON RHORHOR mn Rc4Rd4 HNR'd4Rc4 Compounds of Formula (I) can be prepared as shown in Scheme 9 . Diol-containing intermediate 9-4 can be elaborated to carboxylic acid intermediate 9-1by reaction with a suitable oxidizing agent (e.g., by reaction with oxygen or air over a metal, such as Pt). Carboxylic acid containing intermediate 9-1 can be subjected to conditions for esterification (e.g., refluxing in an alcoholic solvent such as methanol or ethanol in the presence of an acid, such as sulfuric acid) to provide ester intermediate 9-2 . Exposure of 9-2 to an organometallic reagent R-M (e.g., a Grignard reagent such as methylmagnesium bromide) can provide substituted diol intermediate 9-3 . Alternatively, diol-containing intermediate 9-4 can be converted to an aldehyde intermediate 9-5 by treatment with an appropriate oxidizing agent (e.g., sulfur trioxide-pyridine complex or Dess-Martin periodinane). Exposure of aldehyde 9- 5 to an appropriate nucleophile (e.g,. an organometallic reagent R-M such as a Grignard reagent (e.g., methylmagnesium bromide) or reagents providing a source of a fluorinated carbon nucleophile (e.g., an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difluoromethyl)silane in the presence of TBAF)) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 can provide substituted diol intermediate 9-6 . Intermediate 9-6 can be oxidized to ketone 9-7 by reaction with an appropriate oxidizing agent (e.g., Dess Martin periodinane or PCC) and the product ketone 9-7 can be reacted with an appropriate nucleophile (e.g,. an organometallic reagent R-M such as a Grignard reagent (e.g., methylmagnesium bromide) or reagents providing a source of a fluorinated carbon nucleophile (e.g., an appropriately substituted silane such as trimethyl(trifluoromethyl)silane or trimethyl(difluoromethyl)silane in the presence of TBAF)) to provide substituted diol-containing intermediate 9-8 . Intermediates 9- 3 , 9-6 , and 9-8 are useful for the synthesis of compounds of Formula (I) according to the methods of Scheme 1 . Scheme 9.
Compounds of Formula (I) can be prepared as shown in Scheme 10 . Appropriate starting material 10-1 , wherein Y and Y are independently suitable halogens (e.g., Cl, Br or I) or pseudohalogens (e.g., OTf), can be converted to ketone intermediate 10-2 by formation of a Grignard reagent (e.g., by reacting 10-1 with magnesium in the presence of dibromoethane), and reaction of the Grignard reagent with a suitable electrophile (RCO-L), Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 wherein L is a suitable leaving group (e.g., RCO-L is a Weinreb amide (L = –NMeOMe), such as 2,2-difluoro-N-methoxy-N-methylacetamide). Intermediate 10-2 can be converted to an appropriately substituted olefin 10-3 via known methods (e.g., by reaction with trimethylsilyldiazomethane in the presence of a catalyst such as tris(triphenylphosphine)rhodium(I) chloride and triphenylphosphine in a mixture containing 2-propanol; or via Peterson olefination, e.g., reaction with ((trimethylsilyl)methyl)magnesium chloride followed by reaction with trimethylsilyl trifluoromethaneesulfonate)). Intermediate 10-3 can be converted to compounds of Formula (I) as shown in Scheme 1 . Scheme 10.
The reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, (e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. The expressions, "ambient temperature" or "room temperature" or "rt" as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Preparation of compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999). Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., H or C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography. Methods of Use The compounds, salts or stereoisomers thereof described herein inhibit activity of PI3Kγ kinase. Accordingly, the compounds, salts or stereoisomers described herein can be used in methods of inhibiting PI3Kγ kinase by contacting the kinase with any one or more of the compounds, salts, or compositions described herein. In some embodiments, the compounds or salts can be used in methods of inhibiting activity of PI3Kγ in an individual/patient in need of the inhibition by administering an effective amount of a compound or salt of described herein. In some embodiments, modulating is inhibiting. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo. Advantageously, the compounds as described herein demonstrate better efficacy and favorable safety and toxicity profiles in animal studies. In some embodiments, the PI3Kγ includes a mutation. A mutation can be a replacement of one amino acid for another, or a deletion of one or more amino acids. In such embodiments, the mutation can be present in the kinase domain of the PI3Kγ. In some embodiments, the compound or salt further inhibits PI3Kδ. The compounds or salts described herein can be selective. By "selective" is meant that the compound binds to or inhibits PI3Kγ with greater affinity or potency, respectively, compared to at least one other kinase. In some embodiments, the compounds of the disclosure are selective inhibitors of PI3Kγ over PI3Kδ, PI3Kα, and PI3Kβ. In some embodiments, the compounds of the disclosure are selective inhibitors of PI3Kγ over PI3Kα and PI3Kβ. In some embodiments, selectivity can be at least about 2-fold, 3-fold, 5-fold, 10-fold, at or 20-fold over PI3Kδ as measured by the assays described herein. In some embodiments, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 selectivity can be tested at the 2 μM ATP concentration of each enzyme. In some embodiments, the selectivity of compounds of the disclosure can be determined by cellular assays associated with particular PI3K kinase activity. Another aspect of the present disclosure pertains to methods of treating a kinase PI3Kγ-associated disease or disorder in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of one or more compounds of the present disclosure or a pharmaceutical composition thereof. A PI3Kγ-associated disease or disorder can include any disease, disorder or condition that is directly or indirectly linked to expression or activity of the PI3Kγ, including overexpression and/or abnormal activity levels. In some embodiments, the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease. In some embodiments, the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, head and neck squamous cell carcinoma, prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma. In some embodiments, the sarcoma is Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma. In some embodiments, the disease or disorder is mesothelioma or adrenocarcinoma. In some embodiments, the disease or disorder is mesothelioma. In some embodiments, the disease or disorder is adrenocarcinoma. In some embodiments, the disease or disorder is acute myeloid leukemia (e.g., acute monocytic leukemia), small lymphocyctic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell actute lymphoblasic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma. In some embodiments, the mature (peripheral) t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 NK-cell leukemia, mycosis fungoides/Sezary syndrome, naplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma In some embodiments, the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL. In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xenoderoma pigmentosum, keratoctanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma. In some embodiments, the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smouldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma. MDSC (myeloid-derived suppressor cells) are a heterogenous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells). MDSCs strongly expand in pathological situations such as chronic infections and cancer, as a result of an altered haematopoiesis. MDSCs are discriminated from other myeloid cell types in which they possess strong immunosuppressive activities rather than immunostimulatory properties. Similar to other myeloid cells, MDSCs interact with other immune cell types including T cells, dendritic cells, macrophages and natural killer cells to regulate their functions. In some embodiments, the compounds, etc. described herein can be used in Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 methods realted to cancer tissue (e.g., tumors) with high infiltration of MDSCs, including Solid tumors with high basal level of macrophage and/or MDSC infiltration. In some embodiments, the non-Hodgkin’s lymphoma (NHL) is relapsed NHL, refractory NHL, recucurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL). In some embodiments, the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.In some embodiments, the Burkitt’s lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma. In some embodiments, the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy (e.g, allergic rhinitis), pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis), thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren’s syndrome, osteoarthritis, restenosis, or atherosclerosis. In some embodiments, the disease or disorder is heart hypertropy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), idiopathic pulmonary fibrosis, autoimmune hemolytic anemia, vasculitis, lupus nephritis, pemphigus, or membranous nephropathy. In some embodiments, disease or disorder is heart hypertropy, cardiac myocyte dysfunction, chronic obstructive pulmonary disease (COPD), elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia (e.g., hemolytic anemia, aplastic anemia, or pure red cell anemia), bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft rejection, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy. In some embodiments, the disease or disorder is Alzheimer's disease, central nervous system trauma, or stroke.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 In some embodiments, the idiopathic thrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP. In some embodiments, the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV). The present disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein. The present disclosure further provides use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3K with a compound of the disclosure includes the administration of a compound of the present disclosure to an individual or patient, such as a human, having a PI3K, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing the PI3K. It is believed that compounds of provdied herein (e.g., compounds of Formula (I), or pharmaceutically acceptable salts thereof) or any of the embodiments thereof, may possess satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolism and pharmacokinetic properties, solubility, and permeability. It will be understood that determination of appropriate biopharmaceutical properties is within the knowledge of a person skilled in the art, e.g., determination of cytotoxicity in cells or inhibition of certain targets or channels to determine potential toxicity. As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 As used herein, the term "treating" or "treatment" can refer to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. Combination Therapies Cancer cell growth and survival can be impacted by multiple signaling pathways. Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment. The compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors or one or more therapies for the treatment of diseases, such as cancer. Examples of diseases and indications treatable with combination therapies include those as described herein. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399. Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for treatment of diseases, disorders, or conditions, particularly PI3K-associated diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 For example, the compounds as disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of cancer and other diseases or disorders described herein: Akt1, Akt2, Akt3, TGF- E R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF D R, PDGF E R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and other diseases and disorders described herein include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110 ) , an IDO inhibitor (e.g., epacadostat, NLG919, or BMS-986205), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a Pim inhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), a histone deacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) and an adenosine receptor antagonist or combinations thereof. In some embodiments, the compound or salt described herein is administered with a PI3Kδ inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor. In some embodiments, the compound or salt described herein is administered with a JAK1 inhibitor, which is selective over JAK2. Example antibodies for use in combination therapy include but are not limited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A), Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) and antibodies directed to c-MET. One or more of the following agents may be used in combination with the compounds of the present disclosure and are presented as a non-limiting list: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSATM(gefitinib), 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 TARCEVATM (erlotinib), antibodies to EGFR, GLEEVEC™ (imatinib mesylate), intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™ (oxaliplatin), pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, HERCEPTINTM (trastuzumab), BEXXARTM (tositumomab), VELCADETM (bortezomib),ZEVALINTM (ibritumomab tiuxetan), TRISENOXTM (arsenic trioxide), XELODATM (capecitabine), vinorelbine, porfimer, ERBITUXTM (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731. The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumortargeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS- 207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, Toll receptor agonists, STING agonists, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, rucaparib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, niraparib, veliparib, talazoparib and zoledronate. Additional examples of chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like. Example steroids include corticosteroids such as dexamethasone or prednisone. Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491. Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts. Other example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120. Example suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and their pharmaceutically acceptable salts. Other example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444. Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098,and their pharmaceutically acceptable salts. Other example 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402. In some embodiments, the compounds of the disclosure can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors. In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic in the treatment of cancer, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects. In some embodiments, the compounds of the disclosure can be used in combination with a chemotherapeutic provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma, can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable outcomes of combining a PI3K inhibitor of the present disclosure with an additional agent. In some embodiments, PI3Kγ inhibitors provided herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of cancer as described herein. In one embodiment, the combination with one or more immune checkpoint inhibitors as described herein can be used for the treatment of melanoma. Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7- H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT and VISTA. In some 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 embodiments, the compounds of the disclosure provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. In some embodiments, the PI3Kγ inhibitors provided herein can be used in combination with one or more agonists of immune checkpoint molecules, e.g., OX40, CD27, OX40, GITR, and CD137 (also known as 4-1BB). In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PDantibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is MGA012. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In some embodiments, the PI3Kγ inhibitors provided herein can be used alone, or in combination an anti-PD-1, for the treatment melanoma (PD-1 refractory), NSCLC (PD-1 refractory), HNSCC (PD-1 refractory), triple negative breast cancer (PD-1 naïve), mesothelioma, adrenocarcinoma or tumors with high level of MDSC. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136. In some embodiments, the inhibitor is MCLA-145. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab AGEN1884, or CP-675,206.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873. In some embodiments, the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab. The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, PI3K-gamma inhibitors provided herein can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase. Examples of IDOinhibitors include epacadostat, BMS-986205, PF-06840003, IOM2983, RG-70099, LY338196, and NGL919. In some embodiments, the compounds of the disclosure can be used in combination with an inhibitor of JAK or PI3K G . The agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms. The compounds of the present disclosure can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infections. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the compounds of the disclosure where the dexamethasone is administered intermittently as opposed to continuously. The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF. The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses. The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness. In some further embodiments, combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant. The compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin. The compounds of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus. Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria. Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum. Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the present compound in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms. Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds of the disclosure can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. This disclosure also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions of the disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. The compounds of the disclosure may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the disclosure can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the compositions of the disclosure contain from about 5 to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient. In some embodiments, the compositions of the disclosure contain from about 50 to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient. In some embodiments, the compositions of the disclosure contain from about 500 to about 1000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient. Similar dosages may be used of the compounds described herein in the methods and uses of the disclosure. The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present disclosure. The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the compounds and compositions of the present disclosure can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g. glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the disclosure. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of a compound of the present disclosure can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the disclosure in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the disclosure can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. The compositions of the disclosure can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed herein. Labeled Compounds and Assay Methods Another aspect of the present disclosure relates to labeled compounds of the disclosure (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PI3K in tissue samples, including human, and for identifying PI3K ligands by inhibition binding of a labeled compound. Substitution of one or more of the atoms of the compounds of the present disclosure can also be useful in generating differentiated ADME (Adsorption, Distribution, Metabolism and Excretion) Accordingly, the present disclosure includes PI3K assays that contain such labeled or substituted compounds. The present disclosure further includes isotopically-labeled compounds of the disclosure. An "isotopically" or "radio-labeled" compound is a compound of the disclosure where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present disclosure include but are not limited to H (also written as D for deuterium), H (also 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 written as T for tritium), C, C, C, N, N, O, O, O, F, S, Cl, Br, Br, Br, Br, 123I, 124I, 125I and 131I. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a C 1-6 alkyl group of Formula (I) can be optionally substituted with deuterium atoms, such as –CD 3 being substituted for –CH 3). In some embodiments, alkyl groups of the disclosed Formulas can be perdeuterated. One or more constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound presented herein can be replaced or substituted by deuterium (e.g., one or more hydrogen atoms of a C 1-6 alkyl group can be replaced by deuterium atoms, such as –CD 3 being substituted for –CH 3). In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 1-2, 1-3, 1-4, 1-5, o r1-6 deuterium atoms. In some embodiments, all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attached to carbon atoms of any alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl substituents, or -C 1-6 alkyl- linking groups, as described herein, are each optionally replaced by a deuterium atom. Synthetic methods for including isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in various studies such as NMR spectroscopy, metabolism experiments, and/or assays. Substitution with heavier isotopes, such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (see e.g., A. Kerekes et.al. J. Med. Chem. 2011 , 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015 , 58, 308-312). In particular, substitution at one or more metabolism sites may afford one or more of the therapeutic advantages. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PI3K labeling and competition assays, compounds that incorporate H, C, Br, 125I, 131I or 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 35S can be useful. For radio-imaging applications C, F, 125I, 123I, 124I, 131I, Br, Br or Br can be useful. It is understood that a "radio-labeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of H, C, 125I, S and Br. The present disclosure can further include synthetic methods for incorporating radio-isotopes into compounds of the disclosure. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds of disclosure. A labeled compound of the disclosure can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a PI3K by monitoring its concentration variation when contacting with the PI3K, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PI3K (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PI3K directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained. Kits The present disclosure also includes pharmaceutical kits useful, for example, in the treatment or prevention of PI3K-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 The compounds of the Examples have been found to be PI3Kγ inhibitors according to at least one assay described herein. EXAMPLESPreparatory LC-MS purifications of some of the compounds prepared were performed on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in the literature (see e.g. "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004)). The purified compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity analysis under one or both of the following conditions: Instrument = Agilent 1260 LC/MSD; pH 2 method: column = Waters Sunfire C18, 5 μm particle size, 2.1 x 50 mm, mobile phase: A = 0.025% TFA in water and B = acetonitrile, gradient = 2% to 90% B in 4 minutes with flow rate 2.0 mL/minute; pH 10 method: column = Waters XBridge C18, 5 μm particle size, 2.1 x 50 mm, mobile phase: A = 0.05% NH 4OH in water and B = acetonitrile, gradient = 2% to 90% B in 4 minutes with flow rate 2.mL/minute. Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the Examples. Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: pH = 2 purifications: Waters SunfireTM C 18 5 μm, 30 x 100 mm or Waters XBridgeTM C 18 5 μm, 30 x 100 mm column, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 60 mL/minute, the separating gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see e.g. "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6 , 874-883 (2004)). pH = 10 purifications: Waters XBridgeTM C 18 5 μm, 30 x 100 mm column, eluting with mobile phase A: 0.1% NH 4OH in water and mobile phase B: acetonitrile; the flow rate was 60 mL/minute, the separating gradient was optimized for each compound using the Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Compound Specific Method Optimization protocol as described in the literature (see e.g.Blom et al.). Stereochemical Rationale The Sharpless asymmetric dihydroxylation of olefins has been studied extensively, and its basis as a model for enantioselectivity is well established (Sharpless, K.B.; Amberg, W.; Bennani, Y.L.; Crispino, G.A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem., 1992 , 57, 2768-2771; and Kolb, H.C.; VanNieuwenhze, M.S.; Sharpless, K.B. Chem. Rev., 1994, 94, 2483-2547. Briefly, the application of AD-mix-α (containing (DHQ) 2-PHAL) in the dihydroxylation of prop-1-en-2-ylbenzene affords (S)-2-phenylpropane-1,2-diol. Application of AD-mix- E (containing (DHQD) 2-PHAL) in the dihydroxylation of prop-1-en-2-ylbenzene affords (R)-2-phenylpropane-1,2-diol (Sharpless and Kolb, supra). Moreno-Dorado et al. extended the method to the trifluoromethyl case (e.g., (3,3,3-trifluoroprop-1-en-2-yl)benzene affords (S)-3,3,3-trifluoro-2-phenylpropane-1,2-diol when treated with AD-mix-α and affords (R)-3,3,3-trifluoro-2-phenylpropane-1,2-diol when treated with AD-mix- E ) and the stereochemical outcome was verified by subsequent conversion to well known compounds whose specific rotations were found to be in agreement with the literature values (Moreno-Dorado, F.J.; Guerra, F.M.; Ortega, M.J.; Zubia, E.; Massanet, G.M. Tetrahedron: Asymmetry, 2003 , 14, 503-510). While not wishing to be bound by any one theory, in the dihydroxylations performed on vinyl arenes in the Examples, we expect to obtain the (S)- configuration with AD-mix-α and the (R)-configuration with AD-mix- E . Example 1a. 2-(3-(5-Amino-6-(1-(methyl-d 3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4- methylphenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer isolated) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 1. 2-(3-Chloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Cl BOO A degassed mixture of 4-bromo-2-chloro-1-methylbenzene (12.0 g, 58.4 mmol, Aldrich), potassium acetate (17.2 g, 175 mmol), bis(pinacolato)diboron (16.3 g, 64.2 mmol), and PdCl 2(dppf)-CH 2Cl 2 adduct (1.91 g, 2.34 mmol) in dioxane (120 mL) was heated at 75 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered, and solvent was removed in vacuo. Purification via flash chromatography, eluting with a gradient of 0-5% EtOAc in hexanes, afforded product as a white solid (11.7 g, 80%). LCMS for C 13H 19BClO 2 (M+H)+: calculated m/z = 253.1; found 253.0. Step 2. 2-Chloro-1-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene Cl FFF A degassed mixture of 2-(3-chloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.7 g, 46.6 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (11.4 g, 65.2 mmol, Aldrich), K 2CO 3 (1.0 M in water, 140 mL, 140 mmol), and Pd(PPh 3) 2Cl 2 (1.63 g, 2.33 mmol) in THF (300 mL) was heated at 65 °C under N 2 for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, followed by brine, dried over Na 2SO 4, filtered, and solvent was removed in vacuo. Purification via flash chromatography, eluting with hexanes, afforded product as a yellow oil (8.56 g, 83%). H NMR (400 MHz, CDCl 3) δ 7.47 (s, 1H), 7.27 (s, 2H), 6.00 – 5.96 (m, 1H), 5.81 – 5.76 (m, 1H), 2.42 (s, 3H). F NMR (376 MHz, CDCl 3) δ -64.93 (s). Step 3. 2-(3-Chloro-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (enriched in one enantiomer) Cl FFF HOHO Cl FFF HOHO and Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 To a suspension of AD-mix-α (54.4 g, 116 mmol) in water (100 mL) at 0 °C was added a solution of 2-chloro-1-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (8.56 g, 38.mmol) in t-BuOH (100 mL). The mixture was then stirred at 6 °C for 46 hours. The reaction was cooled in an ice bath to 0 °C, and sodium sulfite (18 g) was added. The reaction mixture was warmed to room temperature and stirred for 30 minutes. tert-Butanol was removed in vacuo and the aqueous mixture was extracted twice with EtOAc. The combined organic extracts were dried over Na 2SO 4, filtered, and solvent was removed in vacuo. Purification via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes afforded product as a colorless oil (8.7 g, 88%). Due to use of AD-mix-α, it is believed that the product was enriched in the (S)-enantiomer (see stereochemical rationale supra). H NMR (400 MHz, CDCl 3) δ 7.59 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.31 (dd, J = 11.9, 6.1 Hz, 1H), 3.91 – 3.84 (m, 1H), 3.70 (s, 1H), 2.41 (s, 3H), 1.88 – 1.79 (dd, J = 7.1, 6.3 Hz, 1H). F NMR (376 MHz, CDCl 3) δ -77.25 (s). Step 4. 3,3,3-Trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (enriched in one enantiomer) B FFF HOHO O OB FFF HOHO O O and A degassed mixture of 2-(3-chloro-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (from Step 3, enriched in one isomer (believed to the (S)-enantiomer), 1.00 g, 3.93 mmol), bis(pinacolato)diboron (2.99 g, 11.8 mmol), potassium acetate (2.31 g, 23.6 mmol), Pd 2(dba) (0.180 g, 0.196 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.374 g, 0.785 mmol) in dioxane (12 mL) was heated in a sealed vial in an oil bath held at 120 °C for 2 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite®, and solvent was removed in vacuo. The product was purified via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes to afford product as an oil (1.0 g, 73%). LCMS for C 16H 26BF 3NO 4 (M+NH 4)+: calculated m/z = 364.2; found 364.2 (pH 10 analytical condition).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 5. 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (single enantiomers isolated) FFF HOHOFFF HOHO and NNNN NHClNHCl A degassed mixture of 5-bromo-3-chloropyrazin-2-amine (0.163 g, 0.780 mmol, Ark Pharm), 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)propane-1,2-diol (0.300 g, 0.867 mmol enriched in one isomer (believed to be the (S)- enantiomer) from Step 4), Na 2CO 3 (0.276 g, 2.60 mmol) and PdCl 2(dppf)-CH 2Cl 2 adduct (0.035 g, 0.043 mmol) in dioxane (10 mL) and water (2 mL) was heated to 100 °C overnight. Upon cooling to room temperature, the reaction mixture was diluted with water and EtOAc, and the biphasic mixture was filtered through Celite®. The layers were separated and the aqueous layer was extracted with another portion of EtOAc. Thecombined organic layers were washed with brine, dried over MgSO 4, filtered, and concentrated. Purification via flash chromatography, eluting with a gradient of 0-70% EtOAc/hexanes afforded product as an oil. LCMS for C 14H 14ClF 3N 3O 2 (M+H)+: calculated m/z = 348.1; found 348.1. The enantiomers were separated by chiral chromatography (Phenomenex Lux Amylose-1, 21.2 x 250 mm, 5 μM, loading: 75 mg in 5.0 mL EtOH, eluting with 45% EtOH in hexanes at 20 mL/min for minutes). Peak 1 retention time: 6.5 min, Peak 2 retention time: 8.9 min. Peak 1 was believed to be the (S)-enantiomer, while Peak 2 was believed to be the (R)-enantiomer. Peak 1 was used in Step 6. Peak 1: H NMR (400 MHz, CDCl 3) δ 8.05 (s, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.12 (s, 2H), 4.26 (d, J = 11.9 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.39 (s, 3H). Peak 2: H NMR (400 MHz, CDCl 3) δ 8.07 (s, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 5.09 (br s, 2H), 4.28 (d, J = 11.9 Hz, 1H), 3.(d, J = 11.9 Hz, 1H), 3.84 (br s, 1H), 2.40 (s, 3H), 2.15 (br s, 1H). Step 6. 2-(3-(5-Amino-6-(1-(methyl-d 3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer prepared) A degassed mixture of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (0.120 g, 0.345 mmol, Peak 1 from Step 5), 1-(methyl-d 3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (219 mg, 1.04 mmol, prepared as in Journal of Labelled Compounds and Radiopharmaceuticals (2012), 55(13), pp.467-469), 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 and PdCl 2(dppf)-CH 2Cl 2 adduct (28 mg, 0.035 mmol) in Na 2CO 3 solution (1.0 M in water, 1.04 mL, 1.04 mmol) and dioxane (3.0 mL) was heated to 100 °C for 5 hours. The mixture was cooled to room temperature, filtered and purified by preparative HPLC-MS (pH = 2). Lyophilization of the eluent afforded product as a white solid (0.200 g, 44%). The product was believed to be the (S)-enantiomer, (S)-2-(3-(5-Amino-6-(1-(methyl-d3)-1H-pyrazol-5- yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, for the reasons detailed above. LCMS calculated for C 18H 16D 3F 3N 5O 2 (M+H)+: m/z = 397.2, found: 397.1. H NMR (600 MHz, DMSO-d 6) δ 8.20 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.(d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.39 (br s, 2H), 3.90 (s, 2H), 2.39 (s, 3H). Example 1b. 2-(3-(5-Amino-6-(1-(methyl-d 3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4- methylphenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer isolated) The procedure of Example 1a, Step 6, was followed, using Peak 2 from Example 1a, Step 5. A degassed mixture of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol (0.020 g, 0.058 mmol, Peak 2 from Example 1a, Step 5) and 1-(methyl-d 3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.4 mg, 0.1mmol, prepared as in Journal of Labelled Compounds and Radiopharmaceuticals (2012), 55(13), pp.467-469), and PdCl 2(dppf)-CH 2Cl 2adduct (4.7 mg, 5.7 μmol) in dioxane (2 mL) and Na 2CO 3 solution (1.0 M, 0.173 mL, 0.173 mmol) was heated to 100 °C for 5 hours. Upon cooling to room temperature, the reaction mixture was filtered and purified via preparative HPLC-MS (pH = 2) to afford product as a white solid (8.0 mg, 27%). The product was believed to be the (R)-enantiomer, (R)-2-(3-(5-Amino-6-(1-(methyl-d3)-1H-pyrazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, for the reasons detailed above in Example 1a, Step 5. LCMS calculated for C 18H 16D 3F 3N 5O 2 (M+H)+: m/z = 397.2, found: 397.1. H NMR (400 MHz, DMSO-d 6) δ 8.20 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.(d, J = 1.9 Hz, 1H), 7.50 (dd, J = 7.9, 1.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 1.Hz, 1H), 6.37 (br s, 2H), 3.91 (s, 2H), 2.39 (s, 3H). Examples 2-7.Unless otherwise indicated, the compounds in Table 1 were synthesized according to the procedure described for Example 1a, utilizing the appropriate 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 boronic esters or boronic acids. As detailed above, a single enantiomer was isolated and was believed to be the (S)-enantiomer (see stereochemical rationale supra). Table 1.
Example No. Compound Name R LCMS 2 2-(3-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) NN Calculated for C 18H 19F 3N 5O (M+H)+: m/z = 394.1, found: 394. 3 2-(3-(5-Amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(1H-pyrazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) HNN Calculated for C 17H 17F 3N 5O (M+H)+: m/z = 380.1, found: 380. 4 2-(3-(5-Amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(3-methylisoxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) ON Calculated for C 18H 18F 3N 4O (M+H)+: m/z = 395.1, found: 395. 2-(3-(5-Amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(isothiazol-4-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) SN Calculated for C 17H 16F 3N 4O 2S (M+H)+: m/z = 397.1, found: 397.1 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example No. Compound Name R LCMS 6 2-(3-(5-Amino-6-(isothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(isothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt) SN Calculated for C 17H 16F 3N 4O 2S (M+H)+: m/z = 397.1, found: 397. 7 2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-amino-6-(3-methylisothiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) SN Calculated for C 18H 18F 3N 4O 2S (M+H)+: m/z = 411.1, found: 411.
Example 9. 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer prepared) Step 1. 2-(3-Chloro-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (racemic mixture prepared) Cl FFF HOHO To a solution of 2-chloro-1-methyl-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.00 g, 13.6 mmol, prepared as in Example 1a, Step 2) in acetone (30 mL) and water (30 mL) was added NMO (2.07 g, 17.7 mmol) and OsO 4 (4% in water, 5.19 mL, 0.816 mmol). The reaction was stirred for 5 hours. The reaction mixture was filtered and concentrated. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with two additional portions of EtOAc. The combined organic layers were dried over Na 2SO 4, filtered and concentrated. Purification via flash chromatography, eluting with a gradient of 0-50% EtOAc in hexanes afforded product as an oil (2.86 g, 76%).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 2. 3,3,3-Trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (racemic mixture prepared) B FFF HOHO O O A degassed mixture of 2-(3-chloro-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (racemic mixture from Step 1, 1.00 g, 3.93 mmol), bis(pinacolato)diboron (2.99 g, 11.8 mmol), potassium acetate (2.31 g, 23.6 mmol), Pd 2(dba) 3 (0.180 g, 0.196 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.374 g, 0.785 mmol) in dioxane (12.0 mL) was heated in a sealed vial in an oil bath at 120 °C for 1.5 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite®, and the solvent was removed in vacuo. The product was purified via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes to afford product as an oil (1.0 g, 73%). LCMS for C 16H 26BF 3NO 4 (M+NH 4)+: calculated m/z = 364.2; found 364.2 (pH 10 analytical condition). Step 3. (S)-2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol and (R)-2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane- 1,2-diol (single enantiomers isolated) FFF OHOH N N HN Cl FFF OHOH N N HN Cl and A vial was charged with 5-bromo-3-chloropyrazin-2-amine (0.379 g, 1.82 mmol, Ark Pharm), and 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (0.700 g, 2.02 mmol) and dioxane (30 mL). The reaction was degassed, a mixture of Na 2CO 3 (0.643 g, 6.07 mmol) in water (10 mL) was added, followed by PdCl 2(dppf)-CH 2Cl 2 adduct (0.083 g, 0.101 mmol), and the mixture was degassed again. The reaction was heated to 100 °C overnight. Upon cooling to room temperature, the reaction mixture was diluted and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and solvent was removed in vacuo. 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Purification via flash chromatography, eluting with a gradient of 0-100% EtOAc in hexanes afforded product as a light yellow oil (506 mg, 72%). The enantiomers were separated by chiral chromatography (Phenomenex Lux Amylose-1, 21.2 x 250 mm, 5 μM, loading: 45 mg in 1.8 mL EtOH, eluting with 45% EtOH in hexanes at 20 mL/min for 10 minutes). Peak retention time: 6.0 min, Peak 2 retention time: 7.7 min. Peak 1 was used in Step 4. Peak 1 was believed to be the (S)-enantiomer, based on the same separation conditions that were used in Example 1a, Step 5. LCMS for C 14H 14ClF 3N 3O 2 (M+H)+: calculated m/z = 348.1; found 348.1. Step 4. 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer prepared) A degassed mixture of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (100 mg, 0.288 mmol, Peak 1 from Step 3), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (0.180 g, 0.863 mmol, Ark Pharm) and PdCl 2(dppf)-CH 2Cl 2 adduct (23.5 mg, 0.029 mmol) in dioxane (3 mL) and Na 2CO 3 solution (1.0 M in water, 0.86 mL, 0.86 mmol) was heated in a sealed vial in an oil bath held overnight at 120 °C. Based on the determination in Step 3, the product is believed to be the (S)-enantiomer. Preparative HPLC-MS (pH = 2) afforded product as a light yellow solid (0.080 g, 54%). The product is believed to be the (S)-enantiomer, (S)-2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol. LCMS calculated for C 18H 18F 3N 4O 3 (M+H)+: m/z = 395.1, found: 395.1. H NMR (500 MHz, DMSO-d 6) δ 8.15 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.Hz, 1H), 3.92 (s, 2H), 2.54 (s, 3H), 2.36 (s, 3H). Examples 10 and 11.Unless otherwise indicated, the compounds in Table 2 were synthesized according to the procedure described for Example 9, utilizing the appropriate boronic esters or boronic acids. While not wishing to be bound by any theory, it is thought that the compounds below are the (S)-enantiomer.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Table 2.
Example No. Compound Name R LCMS H NMR 2-(3-(5-Amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(2-methylthiazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) S N Calculated for C 18H 18F 3N 4O 2S (M+H)+: m/z = 411.1, found: 411.1H NMR (600 MHz, DMSO-d 6) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.63 (s, 1H), 7.(d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.61 (s, 2H), 3.92 (s, 2H), 2.68 (s, 3H), 2.40 (s, 3H). 11 2-(3-(5-Amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(oxazol-5-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) O N Calculated for C 17H 16F 3N 4O (M+H)+: m/z = 381.1, found: 381.1H NMR (500 MHz, DMSO-d 6) δ 8.56 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.(s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 3.92 (s, 2H), 2.38 (s, 3H). Example 12. 2-(3-(5-Amino-6-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer prepared) A mixture of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (17 mg, 0.049 mmol, Peak 1 from Example 1a, Step 5; due to use of AD-mix-α in Step 3 of Example 1a that later produced Peak 1 of Example 1a, Step 5, it is believed that the reactant here is the (S)-enantiomer of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (see stereochemical rationale supra), 1H- pyrazole (10.0 mg, 0.147 mmol), and cesium carbonate (48 mg, 0.15 mmol) in dioxane (1 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 mL) was heated in an oil bath held at 120 °C overnight. Upon cooling to room temperature, the mixture was diluted with MeOH and filtered. Purification via preparative HPLC-MS (pH 2) afforded the desired product as a white solid (5.0 mg, 20%). The product is believed to be the (S)-enantiomer, (S)-2-(3-(5-Amino-6-(1H-pyrazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol. LCMS calculated for C 17H 17F 3N 5O 2 (M+H)+: m/z = 380.1, found: 380.1. H NMR (400 MHz, DMSO-d 6) δ 8.63 (dd, J = 2.6, 0.5 Hz, 1H), 8.19 (s, 1H), 7.94 – 7.92 (m, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.51 (dd, J = 8.0, 1.4 Hz, 1H), 7.34 (d, J = 8.Hz, 1H), 6.66 (dd, J = 2.5, 1.9 Hz, 1H), 3.93 (s, 2H), 2.43 (s, 3H). F NMR (376 MHz, DMSO-d 6) δ -74.79 (s), -75.54 (s). Examples 13-15.Unless otherwise indicated, the compounds in Table 3 were synthesized according to the procedure described for Example 12, utilizing the appropriate heterocycles. As detailed above, due to use of AD-mix-α in Step 3 of Example 1a that later produced Peak of Example 1a, Step 5, it is believed the products in the table below are the (S)-enantiomer. Table 3.
Example No. Compound Name R LCMS 13 2-(3-(5-Amino-6-(1H-1,2,3-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(1H-1,2,3-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) NNN Calculated for C 16H 16F 3N 6O (M+H)+: m/z = 381.1, found: 381. 14 2-(3-(5-Amino-6-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(2H-1,2,3-triazol-2-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) NNN Calculated for C 16H 16F 3N 6O (M+H)+: m/z = 381.1, found: 381. 2-(3-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol, trifluoroacetate salt (single enantiomer isolated, believed to be (S)-2-(3-(5-Amino-6-(1H-1,2,4-triazol-1-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol) NNN Calculated for C 16H 16F 3N 6O (M+H)+: m/z = 381.1, found: 381.1 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 16. 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d 3)phenyl)- 3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer prepared) Step 1. 2,2,2-Trifluoro-1-(4-(methyl-d 3)phenyl)ethan-1-one CD OFFF 1,4-Dibromobenzene (10.0 g, 42.4 mmol, Aldrich) in THF (94 mL) and diethyl ether (94 mL) at -78 °C was treated dropwise with n-butyllithium (1.6 M in hexanes, 26.5 mL, 42.mmol). Ethyl 2,2,2-trifluoroacetate (6.02 g, 42.4 mmol, Aldrich) was then added, and the reaction was stirred for 30 minutes. A further portion of n-butyllithium (1.6 M in hexanes, 26.5 mL, 42.4 mmol) was added, and after stirring for 10 minutes, iodomethane-d 3 (6.76 g, 46.6 mmol, Aldrich) was added. After stirring for 30 minutes, a precooled solution of conc. HCl (12.5 mL) in EtOH (6.25 mL) was added. The reaction mixture was then poured into 2 N HCl (250 mL). The layers were separated and the organic layer was dried over MgSO 4, filtered and concentrated to afford product, which was used without further purification. Yield: 7.2 g, 89%. H NMR (400 MHz, CDCl 3) δ 8.00 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H). F NMR (376 MHz, CDCl 3) δ -71.33 (s). Step 2. 1-(3-Bromo-4-(methyl-d 3)phenyl)-2,2,2-trifluoroethan-1-one CD OFFF Br A solution of 2,2,2-trifluoro-1-(4-(methyl-d 3)phenyl)ethan-1-one (7.20 g, 37.7 mmol) in 1,2-dichloroethane (10 mL) was added slowly dropwise to a mixture of aluminum chloride (11.0 g, 82.9 mmol) in 1,2-dichloroethane (25 mL). The reaction mixture was then heated to q C and was stirred for 5 minutes. Bromine (1.94 mL, 37.7 mmol) was then added dropwise to the heated mixture. The reaction was stirred at 35 q C for 1.5 hours, then at 45 q C for hours. Upon cooling to room temperature, the reaction was quenched by slowly pouring into a Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 mixture of ice-cold DCM and 1 N HCl. The layers were separated, and the aqueous layer was extracted with two further portions of DCM. The combined organic extracts were washed with sat. NaHCO 3 solution, followed by brine, dried over Na 2SO 4, filtered and concentrated to afford product, which was used without further purification. (Yield: 9.9 g, 98%). H NMR (400 MHz, CDCl 3) δ 8.28 – 8.22 (m, 1H), 7.96 – 7.89 (m, 1H), 7.44 (d, J = 8.0 Hz, 1H). F NMR (376 MHz, CDCl 3) δ -71.50 (s). Step 3. 2-Bromo-1-(methyl-d 3)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene CD FFF Br A mixture of methyltriphenylphosphonium bromide (12.4 g, 34.7 mmol) in THF (mL) at 0 °C was treated with n-butyllithium (1.6 M in hexanes, 20.8 mL, 33.3 mmol) added dropwise, and the reaction was stirred for 20 minutes. A solution of 1-(3-bromo-4-(methyl-d 3)phenyl)-2,2,2-trifluoroethan-1-one (7.50 g, 27.8 mmol) in THF (15 mL) was added dropwise, and the cooling bath was removed. The mixture was allowed to reach room temperature and stir for 2.5 hours. The reaction mixture was diluted with water and extracted three times with DCM. The combined organic extracts were dried over Na 2SO 4, filtered and solvent was removed in vacuo. Purification via flash chromatography (eluting with a slow gradient from 0-10% EtOAc in hexanes) afforded product as a yellow oil (2.3 g, 23%). H NMR (400 MHz, CDCl 3) δ 7.65 (d, J = 1.3 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.27 (d, J = 7.9 Hz, 1H), 5.98 (q, J = 1.2 Hz, 1H), 5.78 (q, J = 1.5 Hz, 1H). F NMR (376 MHz, CDCl 3) δ -64.(s). Step 4. 2-(3-Bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2-diol (enriched in one enantiomer) CD FFF Br HOHO CD FFF Br HOHO and To a suspension of AD-mix-α (18.1 g, 38.7 mmol) in water (36 mL) at 0 °C was added a solution of 2-bromo-1-(methyl-d 3)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.46 g, 12.9 mmol) in tBuOH (36 mL). The mixture was stirred at 6 °C for 88 hours. The reaction was warmed to room temperature and sodium sulfite (6.0 g) was added. After stirring for minutes, tBuOH was removed in vacuo. The aqueous mixture was then extracted twice with EtOAc. The combined organic extracts were dried over Na 2SO 4, filtered and solvent was Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 removed in vacuo. Purification via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, afforded product (3.2 g, 82%). Due to use of AD-mix-α, it is believed that the product is enriched in the (S)-enantiomer (see stereochemical rationale supra). H NMR (400 MHz, CDCl 3) δ 7.78 (d, J = 1.4 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 4.29 (dd, J = 11.9, 6.1 Hz, 1H), 3.91 – 3.82 (m, 1H), 3.77 (s, 1H), 2.00 (t, J = 6.7 Hz, 1H). F NMR (376 MHz, CDCl) δ -77.24 (s). Step 5. 3,3,3-Trifluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (enriched in one enantiomer) CD FFF B HOHO CD FFF B HOHO and O O O O A degassed mixture of 2-(3-bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2- diol (enriched in one enantiomer, believed to be the (S)-isomer as detailed above) from Step 4, 0.50 g, 1.6 mmol), bis(pinacolato)diboron (1.05 g, 4.14 mmol), potassium acetate (0.975 g, 9.93 mmol) and triphenylphosphine palladium chloride (0.070 g, 0.099 mmol) in THF (6.mL) was heated in a sealed vial in an oil bath held at 120 °C for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc and water and filtered. The layers of the filtrate were separated and the organic layer was dried over Na 2SO 4, filtered, and concentrated. Purification via flash chromatography, eluting with a gradient of 0-40% EtOAc/hexanes afforded product (0.39 g, 67%). LCMS for C 16H 23D 3BF 3NO 4 (M+NH 4)+: calculated m/z = 367.2; found 367.2 (pH 10 analytical condition). LCMS for C 16H 19D 3BF 3NaO 4 (M+Na)+: calculated m/z = 372.2; found 372.1 (pH 10 analytical condition). H NMR (400 MHz, CDCl 3) δ 7.92 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.1, 1.8 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.31 (d, J = 11.5 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.64 (s, 1H), 1.37 (s, 12H). Step 6. 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-(methyl-d3)phenyl)-3,3,3-trifluoropropane-1,2-diol (enriched in one enantiomer) CD FFF OHOH N N HN ClCD FFF OHOH N N HN Cland Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 A degassed mixture of 5-bromo-3-chloropyrazin-2-amine (291 mg, 1.40 mmol, Ark Pharm), and 3,3,3-trifluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (a mixture enriched in one enantiomer, believed to be the (S)- isomer from Step 5, 390 mg, 1.11 mmol) in dioxane (16 mL) was treated with Na 2CO solution (1.0 M, 4.2 mL, 4.2 mmol) and PdCl 2(dppf)-CH 2Cl 2 adduct (57 mg, 0.070 mmol). The mixture was degassed again and then heated to 100 °C for 3 hours. Upon cooling to room temperature, the reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted with two additional portions of EtOAc and the the combined organic extracts were washed with brine, dried over Na 2SO 4, filtered, and concentrated. Purification via flash chromatography, eluting with a gradient of 0-80% EtOAc/hexanes afforded product (0.217 g, 56%). LCMS for C 14H 11D 3ClF 3N 3O 2 (M+H)+: calculated m/z = 351.1; found 351.0. H NMR (400 MHz, CDCl 3) δ 8.03 (s, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.50 (dd, J = 8.1, 1.3 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 5.25 (s, 2H), 4.21 (d, J = 11.9 Hz, 1H), 3.97 (d, J = 11.9 Hz, 1H). F NMR (376 MHz, CDCl 3) δ -77.27 (s). The enantiomers were separated by chiral chromatography (Phenomenex Lux Amylose-1, 21.2 x 250 mm, 5 μM, loading: 90 mg in 1.9 mL EtOH, eluting with 30% EtOH in hexanes at mL/min for 20 minutes). Peak 1 retention time: 8.7 min, Peak 2 retention time: 13.5 min. Peak 1 was used in Step 7. Peak 1 was believed to be the (S)-enantiomer (see previous steps). Step 7. 2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2-diol trifluoroacetate salt (single enantiomer prepared) The title compound was prepared according to the procedure of Example 9, Step 4, using Peak 1 from Step 6 of Example 16. LCMS for C 18H 15D 3F 3N 4O 3 (M+H)+: calculated m/z = 398.1; found 398.1. The product is believed to be the (S)-enantiomer, (S)-2-(3-(5-Amino-6-(2-methyloxazol-5-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-3,3,3-trifluoropropane-1,2-diol. H NMR (400 MHz, MeOD) δ 8.14 (s, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.64 (s, 1H), 7.57 (dd, J = 7.9, 1.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 4.09 (d, J = 11.7 Hz, 1H), 4.01 (d, J = 11.7 Hz, 1H), 2.61 (s, 3H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 17. 3-Amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2- yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer prepared) Step 1. Ethyl 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2- yl)phenyl)pyrazine-2-carboxylate 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2-diol (0.200 g, 0.570 mmol; from Example 16, Peak 1 from Step 6, believed to be the (S)- isomer), ethanol (3 mL), triethylamine (0.32 mL, 2.3 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (47 mg, 0.0mmol) were combined in a sealable reaction vessel. Carbon monoxide was bubbled through the reaction mixture subsurface for 5 minutes, then the reaction was sealed and a balloon of CO was affixed. The reaction mixture was heated at 80 °C under an atmosphere of CO for hours. The volatiles were removed in vacuo and the resulting residue was purified via flash chromatography (eluting with a gradient from 0-80% in EtOAc in hexanes) to provide product as a colorless oil (0.15 g, 67%). LCMS for C 17H 16D 3F 3N 3O 4 (M+H)+: calculated m/z = 389.1; found 389.1.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 2. 3-Amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxylic acid To a solution of ethyl 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxylate (0.150 g, 0.386 mmol) in methanol (3 mL) was added lithium hydroxide (46 mg, 1.9 mmol) in water (3.0 mL). The reaction mixture was stirred for 2 hours, and then methanol was removed in vacuo. 1.0 N HCl solution was added to achieve pH = 7 and the resulting mixture was extracted with two portions of EtOAc. The combined organic extracts were dried over MgSO 4, filtered, and concentrated to afford product, which was used without further purification (0.14 mg crude, 100%). LCMS for C 15H 12D 3F 3N 3O 4 (M+H)+: calculated m/z = 361.1; found 361.1. Step 3. 3-Amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide, trifluoroacetate salt To a solution of 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxylic acid (0.050 mg, 0.14 mmol) in DMF (4 mL) was added HATU (79 mg, 0.21 mmol) and DIEA (0.048 mL, 0.28 mmol). To this mixture was added tetrahydro-2H-pyran-4-amine (17 mg, 0.17 mmol, Combi-Blocks). The reaction mixture was stirred for 1 hour, then was diluted with water and extracted with two portions of EtOAc. The combined organic extracts were evaporated and the resulting residue was purified via preparative HPLC-MS (pH = 2) to afford product as a light yellow solid (0.030 g, 38%). The product is believed to be the (S)- isomer (see stereochemical rationale supra). LCMS for C 20H 21D 3F 3N 4O 4 (M+H)+: calculated m/z = 444.2; found 444.4. H NMR (500 MHz, DMSO) δ 8.41 – 8.37 (s, 1H), 8.35 – 8.30 (d, J = 8.3 Hz, 1H), 7.65 – 7.61 (d, J = 2.0 Hz, 1H), 7.55 – 7.51 (dd, J = 8.0, 2.0 Hz, 1H), 7.36 – 7.31 (d, J = 8.0 Hz, 1H), 4.06 – 3.97 (m, 1H), 3.97 – 3.90 (m, 2H), 3.88 – 3.81 (m, 2H), 3.44 – 3.35 (td, J = 11.6, 2.3 Hz, 2H), 1.78 – 1.69 (m, 2H), 1.69 – 1.57 (qd, J = 11.3, 4.3 Hz, 2H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 18. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl- d 3)phenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide trifluoroacetate salt (single enantiomer prepared) Step 1. 1-Bromo-4-(methyl-d3)benzene 1,4-Dibromobenzene (15.0g, 63.6 mmol, Aldrich) in THF (280 mL) at -78 °C was treated dropwise with n-butyllithium (1.6 M in hexanes, 39.7 mL, 63.6 mmol). The reaction mixture was stirred for 30 minutes, followed by the addition of iodomethane-d 3 (10.1 g, 69.mmol, Oakwood). After stirring for 30 minutes, the reaction mixture was warmed to room temperature and diluted with diethyl ether. The mixture was washed with water (2x), followed by brine (1x). The organic layer was dried over MgSO 4, filtered, and concentrated to afford product as a yellow oil, that was used without further purification (10.3 g, 93%). H NMR (400 MHz, CDCl 3) δ 7.42 – 7.37 (d, J = 8.1 Hz, 2H), 7.10 – 7.05 (d, J = 8.0 Hz, 2H). Step 2. 2,2-Difluoro-1-(4-(methyl-d3)phenyl)ethan-1-one To a well stirred mixture of Mg powder (1.9 g, 78 mmol, Aldrich) in THF (72.0 mL) was added 1,2-dibromoethane (two drops). After 10 minutes, a solution of 1-bromo-4-(methyl-d 3)benzene (12.4 g, 71.2 mmol, prepared by the method of Step 1) in THF (54.0 mL) was added dropwise. After complete addition, additional 1,2-dibromoethane was added (two drops). The mixture was stirred at ambient temperature for 1.5 hours, and the mixture was Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 then cooled to 0 °C. 2,2-Difluoro-N-methoxy-N-methylacetamide (9.0 g, 65 mmol, Oakwood) in THF (36.0 mL) was added dropwise and after stirring the mixture at 0 °C for 10 minutes, the ice bath was removed. After 40 minutes, the reaction was quenched by the addition of 2.N HCl (315 mL). After quenching, the reaction was stirred for 15 minutes. Et 2O was added and the resulting layers were separated. The aqueous portion was extracted once with Et 2O. The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with a gradient from 0-10% EtOAc in hexanes to afford product as an off-white solid (8.85 g, 79%). H NMR (400 MHz, CDCl 3) δ 8.03 – 7.95 (d, J = 8.4 Hz, 2H), 7.38 – 7.33 (d, J = 8.3 Hz, 2H), 6.45 – 6.02 (t, J = 53.6 Hz, 1H). Step 3. 1-(3-Bromo-4-(methyl-d 3)phenyl)-2,2-difluoroethan-1-one 2,2-Difluoro-1-(4-(methyl-d 3)phenyl)ethan-1-one (8.45 g, 48.8 mmol) was cooled to °C and concentrated H 2SO 4 (26.0 mL, 488 mmol) was slowly added. The reaction mixture was maintainted at 0 °C, and was treated with N-bromosuccinimide (9.12 g, 51.2 mmol) added portionwise, and was stirred for 1 hour. Separately, a mixture of water and MTBE (1:1) was cooled to 0°C, then added slowly to the reaction mixture at 0 °C. The aqueous layer was separated and was extracted with two additional portions of MTBE. The combined organic extracts were washed with 10% Na 2S 2O 3 and brine, dried over MgSO 4, filtered and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-5% EtOAc in hexanes to afford product as a light yellow oil (10.2 g, 83%). H NMR (4MHz, CDCl 3) δ 8.27 – 8.23 (s, 1H), 7.97 – 7.89 (d, J = 7.9 Hz, 1H), 7.43 – 7.39 (d, J = 8.Hz, 1H), 6.41 – 6.10 (t, J = 53.4 Hz, 1H). Step 4. 2-Bromo-4-(3,3-difluoroprop-1-en-2-yl)-1-(methyl-d3)benzene Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Following a similar procedure as found in Organic Letters Vol.4, No.10, 1671-1674, 2002, to a solution of tris(triphenylphosphine)rhodium(I) chloride (3.17 g, 3.42 mmol) and triphenylphosphine (19.2 g, 73.0 mmol) in THF (140 mL) under N 2 was added 2-propanol (5.62 mL, 73.0 mmol, dried over molecular sieves), followed by 1-(3-bromo-4-(methyl-d 3)phenyl)-2,2-difluoroethan-1-one (11.5 g, 45.6 mmol) in THF (42 mL). Then trimethylsilyldiazomethane (2.0 M in ether, 39 mL, 78 mmol) was slowly added to the mixture. After a stirring for 1.5 hours, the mixture was quenched by the dropwise addition of acetic acid (5.2 mL, 91 mmol). The mixture was stirred for 30 minutes and volatiles were then evaporated on a rotary evaporator. The product was purified via flash chromatography, eluting with 100% hexanes, to afford a mixture of product and PPh 3, which was further purified via flash chromatography (eluting with 100% hexanes) to afford product as a light yellow oil (5.80 g, 51%). H NMR (400 MHz, CDCl 3) δ 7.72 – 7.62 (d, J = 1.9 Hz, 1H), 7.– 7.31 (dd, J = 8.0, 1.8 Hz, 1H), 7.30 – 7.23 (m, 1H), 6.55 – 6.19 (t, J = 55.2 Hz, 1H), 5.75 – 5.72 (t, J = 1.9 Hz, 1H), 5.69 – 5.64 (t, J = 2.3 Hz, 1H). Step 5. 2-(3-Bromo-4-(methyl-d3)phenyl)-3,3-difluoropropane-1,2-diol (enriched in one enantiomer) 2-Bromo-4-(3,3-difluoroprop-1-en-2-yl)-1-(methyl-d 3)benzene (5.8 g, 23 mmol) in tBuOH (60.0 mL) was added to a suspension of AD-mix-alpha (32.5 g, 69.6 mmol) in water (60.0 mL) at 0 °C. The mixture was then stirred at 3-oC for 48 hours. The reaction was then quenched by the addition of sodium sulfite (10 g). The mixture was stirred for 10 minutes, then was concentrated via rotary evaporation to remove tBuOH. The aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, to afford product as a colorless oil (5.8 g, 87%). The product is believed to be enriched in the (S)- isomer (see stereochemical rationale supra). LCMS for C 10H 8D 3BrF 2NaO 2 (M+Na)+: calculated m/z = 306.1; found 306.1. H NMR (400 MHz, CDCl 3) δ 7.75 – 7.73 (d, J = 1.9 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.30 – 7.(d, J = 8.0 Hz, 1H), 6.08 – 5.74 (t, J = 55.8 Hz, 1H), 4.22 – 4.15 (dd, J = 12.1, 4.8 Hz, 1H), 3.88 – 3.80 (dd, J = 12.9, 3.7 Hz, 1H), 3.47 – 3.08 (s, 1H). 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 6. 3,3-Difluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (enriched in one enantiomer) A degassed mixture of 2-(3-bromo-4-(methyl-d 3)phenyl)-3,3-difluoropropane-1,2-diol (2.0 g, 7.0 mmol), bis(pinacolato)diboron (3.22 g, 12.7 mmol), potassium acetate (2.07 g, 21.1 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.395 g, 0.563 mmol) in THF (40.0 mL) was heated in a sealed tube in an oil bath held at 120 °C for 1.5 hours. Upon cooling, the reaction mixture was diluted with EtOAc, filtered through Celite®, and was concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-40% EtOAc in hexanes to afford product as a light yellow oil (2.3 g, 99%). LCMS for C 16H 19D 3BF 2O 3 (M+H-H 2O)+: calculated m/z = 314.2; found 314.2. Step 7. 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3-difluoropropane-1,2-diol (single enantiomer isolated, believed to be the (S)- isomer) A degassed mixture of 5-bromo-3-chloropyrazin-2-amine (2.01 g, 9.63 mmol), 3,3- difluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (2.9 g, 8.7 mmol, prepared as in Step 6) and PdCl 2(dppf)-CH 2Cl 2 adduct (0.358 g, 0.4mmol) in Na 2CO 3 solution (1.0 M, 26.3 mL, 26.3 mmol), and dioxane (90.0 mL) was heated to 100 °C in a flask equipped with reflux condenser for 1 hour. Upon cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to afford product as a light yellow solid (1.84 g, 58%). The enantiomers were separated by chiral chromatography (Phenomenex Lux Amylose-1, 21.2 x 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 250 mm, 5 μM, loading: 90 mg in 9.0 mL EtOH, eluting with 45% EtOH in hexanes at mL/min for 16 minutes). Peak 1 retention time: 9.4 min, Peak 2 retention time: 14.1 min. Peak 1 was believed to be the (S)-enantiomer (see stereochemical rationale supra), while Peak was believed to be the (R)-enantiomer. Peak 1 (1.01 g obtained) was used in Step 8. LCMS for C 14H 12D 3ClF 2N 3O 2 (M+H)+: calculated m/z = 333.1; found 333.1. Step 8. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxylic acid (single enantiomer prepared) 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3-difluoropropane-1,2-diol (0.500 g, 1.50 mmol, peak 1 from Step 7), ethanol (20.0 mL), triethylamine (0.838 mL, 6.01 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (123 mg, 0.150 mmol) were combined in a sealable vessel. Carbon monoxide was bubbled through the reaction mixture subsurface for 5 minutes, then the reaction was sealed and a balloon of CO was affixed. The reaction mixture was heated at °C under an atmosphere of CO for 3.5 hours. The volatiles were removed in vacuo and the resulting residue was purified via flash chromatography (eluting with a gradient from 0-70% in EtOAc in hexanes) to provide desired product ester as an oil (0.440 g). LCMS for C 17H 17D 3F 2N 3O 4 (M+H)+: calculated m/z = 371.2; found 371.1. The ester was then dissolved in MeOH (10.0 mL), and LiOH (0.180 g, 7.51 mmol) in water (10.0 mL) was added. After stirring for 1.5 hours, MeOH was removed in vacuo. The aqueous mixture was treated with 1.0 N HCl to adjust to pH = 3. Solid NaCl was added to saturate the solution, and the mixture was extracted with EtOAc (4x). The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated to afford product as a brown solid (386 mg, 75%). LCMS for C 15H 13D 3F 2N 3O 4 (M+H)+: calculated m/z = 343.1; found 343.1. Step 9. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-(4- hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide trifluoroacetate salt (single enantiomer prepared) To a solution of 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxylic acid (5.0 mg, 0.015 mmol) in DMF (0.20 mL) was added HATU (8.3 mg, 0.022 mmol) and DIEA (0.013 mL, 0.073 mmol). To this mixture was added 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 4-aminobicyclo[2.2.1]heptan-1-ol (2.2 mg, 0.018 mmol). After stirring for 30 minutes, the reaction mixture was diluted with acetonitrile and methanol, filtered, and the product was purified via preparative HPLC-MS (pH = 2). The product is believed to be the (S)-enantiomer (see stereochemical rationale supra). Yield: 6.6 mg. LCMS for C 22H 24D 3F 2N 4O 4 (M+H)+: calculated m/z = 452.2; found 452.2. H NMR (400 MHz, DMSO-d 6) δ 8.41 – 8.38 (s, 1H), 8.23 – 8.20 (s, 1H), 7.60 – 7.57 (d, J = 1.9 Hz, 1H), 7.49 – 7.43 (dd, J = 7.9, 2.0 Hz, 1H), 7.– 7.25 (d, J = 8.0 Hz, 1H), 6.42 – 5.99 (t, J = 55.6 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 11.6 Hz, 1H), 2.07 – 1.94 (m, 2H), 1.91 – 1.79 (m, 4H), 1.77 – 1.63 (m, 2H), 1.62 – 1.(m, 2H). F{H} NMR (376 MHz, DMSO-d 6) δ -74.15 (s), -129.17 – -130.48 (d, J F-F = 277.Hz), -133.80 – -135.42 (d, J F-F = 277.4 Hz). Example 19. 3-Amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2- yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (single isomer prepared) Step 1. 2-(3-Bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoro-2-hydroxypropanal 2-(3-Bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoropropane-1,2-diol (5.0 g, 14.9 mmol, from Example 16, Step 4, before chiral separation (enriched in one enantiomer, believed to be the (S)-enantiomer (see stereochemical rationale supra)) in DCM (80 mL) was treated with triethylamine (27.0 mL, 194 mmol) and the mixture was cooled to 0 °C. Sulfur trioxide- Pyridine complex (9.48 g, 59.6 mmol) dissolved in DMSO (67 mL) was added. The reaction mixture was stirred for 10 minutes, the bath was removed, the mixture was warmed to room temperature, and was stirred for 3.5 hours. The mixture was then concentrated via rotary evaporation to remove DCM and triethylamine, and the remaining aqueous mixture was immersed in a water bath and was treated with saturated NaHCO 3 solution until gas evolution 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 ceased. The mixture was saturated with solid NaCl and additional brine was added. The mixture was extracted with one portion of EtOAc (300 mL). The EtOAc extraction was washed with brine, dried over Na 2SO 4, filtered, and concentrated. The residue was mixed with 100 mL acetonitrile and filtered to remove the small amount of solid precipitate. The acetonitrile filtrate was concentrated via rotary evaporation to give 5.20 g of crude product as a light brown foam. Theoretical yield was assumed and the product was used without further purification. Step 2. 2-(3-Bromo-4-(methyl-d 3)phenyl)-1,1,1-trifluorobutane-2,3-diol (two separate diastereomers were isolated that were each subsequently separated into single enantiomers) Methylmagnesium bromide (3.0 M in Et 2O, 27.8 mL, 83 mmol) was added dropwise to a solution of 2-(3-bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoro-2-hydroxypropanal (4.9 g, mmol) in THF (100 mL) at 0 °C. The mixture was warmed to room temperature and was stirred for 4.5 hours. The mixture was then cooled in an ice-water bath and quenched by addition of 1.0 N HCl. After gas evolution ceased, the bath was removed and 1.0 N HCl was added to adjust to pH = 3. The mixture was stirred for 30 minutes, then was extracted with EtOAc (2x). The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with 100% hexanes, then a gradient of 0-15% EtOAc in hexanes to afford two diastereomers: Peak 1, major diastereomer (first to elute): 1.84 g. Peak 2, minor diastereomer (second to elute): 0.62 g. Each diastereomer (each enriched in one enantiomer believed to be the (S)-configuration at the tertiary alcohol, supra) was submitted separately for chiral purification, and only the major enatiomer in each chiral separation (believed to be the (S)-configuration at the tertiary alcohol, supra) was collected. The first diastereomer to elute during the flash chromatography was subjected to chiral HPLC to separate the enantiomers (Phenomenex Lux Amylose-1, 21.2 x 250 mm, μM, loading: 50 mg in 1.0 mL EtOH, eluting with 5% EtOH in hexanes at 20 mL/min for minutes). Peak 1 retention time: 11.3 min, Peak 2 retention time: 12.5 min. Peak 2 was the Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 major enantiomer, and is thus believed to be the (S)-configuration at the tertiary alcohol (see stereochemical rationale supra). This single enantiomer was subsequently used in Step 3. The second diastereomer to elute during the flash chromatography was subjected to chiral HPLC to separate the enantiomers (Phenomenex Lux Amylose-1, 21.2 x 250 mm, μM, loading: 30 mg in 0.9 mL EtOH, eluting with 30% EtOH in hexanes at 20 mL/min for 12 minutes). Peak 1 retention time: 6.25 min, Peak 2 retention time: 10.5 min. Peak 1 was the major enantiomer, and is thus believed to be the (S)- configuration at the tertiary alcohol (see stereochemical rationale supra). Step 3. 1,1,1-Trifluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-2,3-diol (single isomer prepared) A degassed mixture of 2-(3-bromo-4-(methyl-d 3)phenyl)-1,1,1-trifluorobutane-2,3-diol (0.500 g, 1.58 mmol, peak 2 from chiral separation of the first eluting diastereomer from flash chromatography in Step 2), bis(pinacolato)diboron (723 mg, 2.85 mmol), potassium acetate (466 mg, 4.74 mmol) and triphenylphosphine palladium chloride (89 mg, 0.13 mmol) in THF (10.0 mL) was heated in a sealed tube in an oil bath held at 120 °C for 1.5 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite®, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes to afford product as a light yellow oil. Theoretical yield assumed and the product was used in Step 4. Step 4. 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-1,1,1-trifluorobutane-2,3-diol (single isomer prepared) A degassed mixture of 5-bromo-3-chloropyrazin-2-amine (362 mg, 1.74 mmol, Ark Pharm), 1,1,1-trifluoro-2-(4-(methyl-d 3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 yl)phenyl)butane-2,3-diol (574 mg, 1.58 mmol, from Step 3) and PdCl 2(dppf)-CH 2Cl 2 adduct (64 mg, 0.079 mmol) in dioxane (15.0 mL) and Na 2CO 3 solution (1.0 M, 4.74 mL, 4.mmol) was heated to 100 °C for 2 hours. Additional PdCl 2(dppf)-CH 2Cl 2 adduct (64 mg, 0.079 mmol) was added and the mixture was heated for 1.5 hours at 100 °C. Upon cooling to room temperature, the reaction mixture was partitioned between water and EtOAc then the biphasic mixture was filtered through Celite® to remove solids. The layers of the filtrate were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with a gradient from 0-60% EtOAc in hexanes, to afford product as a light yellow solid (466 mg, 81%). LCMS for C 15H 13D 3ClF 3N 3O 2 (M+H)+: calculated m/z = 365.1; found 365.2. Step 5. 3-Amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (single isomer prepared) The title compound was prepared by following the procedures found in Example 17, Steps 1 through 3, using 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-1,1,1- trifluorobutane-2,3-diol from Step 4. The product was purified via preparative HPLC-MS (pH = 10). The product is believed to be the (S)-enantiomer (see stereochemical rationale supra). LCMS for C 21H 23D 3F 3N 4O 4 (M+H)+: calculated m/z = 458.2; found 458.2. H NMR (5MHz, DMSO) δ 8.38 – 8.35 (s, 1H), 8.35 – 8.30 (d, J = 8.3 Hz, 1H), 7.72 – 7.57 (br s, 1H), 7.57 – 7.54 (d, J = 2.0 Hz, 1H), 7.48 – 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.37 – 7.28 (d, J = 8.0 Hz, 1H), 6.39 – 5.77 (br s, 1H), 5.54 – 4.78 (br s, 1H), 4.45 – 4.37 (q, J = 6.3 Hz, 1H), 4.07 – 3.94 (m, 1H), 3.89 – 3.79 (dt, J = 11.4, 3.6 Hz, 2H), 3.47 – 3.36 (td, J = 11.5, 2.3 Hz, 2H), 1.80 – 1.70 (m, 2H), 1.70 – 1.57 (m, 2H), 0.90 – 0.79 (d, J = 6.3 Hz, 3H). F NMR (4MHz, DMSO) δ -69.03 – -75.88 (s). Example 20. 2-(3-(5-Amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl- d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol, trifluoroacetate salt, (a single diastereomer enriched in one enantiomer was prepared) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 1. 2-(3-Bromo-4-(methyl-d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol (two diastereomers isolated, each enriched in one enantiomer) A solution of 2-(3-bromo-4-(methyl-d 3)phenyl)-3,3,3-trifluoro-2-hydroxypropanal (0.30 g, 0.85 mmol, from Example 19, Step 1) in dry THF (1.7 mL) was cooled to 0 °C and trimethyl(trifluoromethyl)silane (0.31 mL, 2.1 mmol) was added. The yellow mixture was treated with TBAF (1.0 M in THF, 0.017 mL, 0.017 mmol) at 0 °C. The reaction was stirred for a few minutes at 0 °C, the ice bath was removed, and the resulting reaction mixture was stirred for 40 minutes, with warming to room temperature. The reaction was re-cooled to °C, and water (0.17 mL, 9.4 mmol) and TBAF (1.0 M in THF, 0.17 mL, 0.17 mmol) were added. The ice bath was removed and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was diluted with brine (20 mL), and was extracted with EtOAc (50 mL). The organic layer was washed with 1.0 N HCl (2 x 25 mL), followed by brine, dried over Na 2SO 4, filtered, and concentrated to afford a yellow oil. The product was purifed via flash chromatography, eluting with a gradient from 0-15% EtOAc in hexanes to afford two separate diastereomers (each enriched in one enantiomer believed to be the (S)-configuration at the tertiary alcohol (see stereochemical rationale supra)). Peak 1 (first to elute): 92 mg, 29%. Peak 2 (second to elute): 68 mg, 22%. Step 2. 1,1,1,4,4,4-hexafluoro-2-(4-(methyl-d3)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-2,3-diol (a single diastereomer enriched in one enantiomer was prepared) The title product was preprared using the procedure of Example 19, Step 3, using 2-(3-bromo-4-(methyl-d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol (92 mg, 0.20 mmol, Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Peak 1 from Step 1), to afford the title compound (15 mg). LCMS for C 17H 23D 3BF 6NO (M+NH 4)+: calculated m/z = 435.2; found 435.2. Step 3. 5-Chloro-3-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-amine A flask was charged with 3-bromo-5-chloropyrazin-2-amine (0.24 g, 1.2 mmol, D-L Chiral Chemicals), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.24 g, 1.2 mmol, Aldrich), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.041 g, 0.058 mmol), and cesium fluoride (0.53 g, 3.5 mmol). tert-Butyl alcohol (6.1 mL) and water (1.6 mL) were added, and the mixture was degassed and heated to oC for 1.5 hours, then at 70 °C overnight, then at 1oC for 1.5 hours. Upon cooling, the reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted with two additional portions of EtOAc and the combined organic layers were washed with brine, dried over MgSO 4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient of 0-10% MeOH in DCM to afford a pale yellow solid (0.14 g, 58%). LCMS for C 8H 9ClN 5 (M+H)+: calculated m/z = 210.1; found 210.1. Step 4. 2-(3-(5-Amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl-d3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol, trifluoroacetate salt (a single diastereomer enriched in one enantiomer was prepared) A microwave vial was charged with 1,1,1,4,4,4-hexafluoro-2-(4-(methyl-d 3)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-2,3-diol (15 mg, 0.029 mmol, from Step 2, a single diastereomer enriched in one enantiomer), 5-chloro-3-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-amine (9.1 mg, 0.043 mmol, from Step 3) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (4.7 mg, 5.8 μmol). THF (0.5 mL) was added, followed by K 2CO 3 solution (1.0 M, 0.086 mL, 0.086 mmol). The reaction mixture was degassed by bubbling a stream of nitrogen through the solution for minutes, and then was heated in the microwave at 130 °C for 30 minutes. The reaction mixture was diluted with acetonitrile and methanol, was filtered and purified via preparative HPLC-MS (pH = 2) to afford product as the TFA salt (3.7 mg). The product is believed to be enriched in the (S)-enantiomer at the tertiary alcohol (see stereochemical rationale supra). LCMS for C 19H 15D 3F 6N 5O 2 (M+H)+: calculated m/z = 465.2; found 465.1. H NMR (4MHz, MeOD) δ 8.04 – 8.00 (s, 1H), 7.95 – 7.92 (s, 1H), 7.74 – 7.70 (s, 1H), 7.60 – 7.54 (d, J Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 = 7.3 Hz, 1H), 7.38 – 7.34 (d, J = 8.2 Hz, 1H), 4.83 – 4.76 (q, J = 7.2 Hz, 1H), 2.46 (s, 3H). F NMR (376 MHz, MeOD) δ -72.13 – -72.41 (s), -75.50 – -75.75 (s), -77.24 – -77.60 (s). Example 21. 2-(3-(5-Amino-6-(3-methyl-1H-pyrazol-4-yl)pyrazin-2-yl)-4-(methyl- d 3)phenyl)-1,1,1,4,4,4-hexafluorobutane-2,3-diol, trifluoroacetate salt (a single diastereomer enriched in one enantiomer was prepared) The title product was prepared using the procedure of Example 20, Steps 2-4, using Peak 2 from Example 20, Step 1 to afford the title compound as a single diastereomer enriched in one enantiomer. The product is believed to be enriched in the (S)-enantiomer at the tertiary alcohol (see stereochemical rationale supra). LCMS for C 19H 15D 3F 6N 5O 2 (M+H)+: calculated m/z = 465.2; found 465.1. H NMR (400 MHz, MeOD) δ 8.02 – 8.01 (s, 1H), 7.– 7.94 (s, 1H), 7.91 – 7.88 (s, 1H), 7.79 – 7.74 (d, J = 8.1 Hz, 1H), 7.34 – 7.30 (d, J = 8.2 Hz, 1H), 4.70 – 4.47 (q, J = 7.0 Hz, 1H), 2.55 – 2.33 (s, 3H). F NMR (376 MHz, MeOD) δ -72.71 – -73.13 (s), -77.33 – -77.52 (s), -77.58 – -78.04 (s). Example 22. 3-Amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxy-3-methylbutan-2- yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide, trifluoroacetate salt, (enriched in one enantiomer) Step 1. 2-(3-Chloro-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (enriched in one enantiomer) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 A procedure similar to that disclosed in Tetrahedron: Asymmetry Vol. 5, No. 8, pp. 1413-1476, 1994 was performed as follows: to a mixture of 2-(3-chloro-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (0.70 g, 2.8 mmol, Example 1a, Step 3 (enriched in one enantiomer, believed to be the (S)- enantiomer, see stereochemical rationale supra)), NaHCO (0.346 g, 4.12 mmol), and Platinum (5% on carbon, 1.07 g, 0.275 mmol) in water (50.0 mL) was added one drop of Antifoam A concentrate, 100% (Aldrich catalog # A5633). The mixture was then heated at 75 °C overnight while a gentle flow of air (pulled into the reaction flask by vacuum) was bubbled through the solution. Additional Platinum (5% on carbon, 0.644 g, 0.165 mmol) was added and the mixture was stirred under the same conditions for a total of 40 hours. Upon cooling to room temperature, the mixture was filtered through Celite® and rinsed with water. 1.0 N HCl was added to achieve pH = 2, and the aqueous mixture was extracted with EtOAc (3x). The combined organic extracts were washed with water, followed by brine, dried over MgSO 4, filtered and evaporated. The product was purified via flash chromatography, eluting with a gradient from 0-100% EtOAc in hexanes to afford a light yellow solid contaminated with unreacted diol. Step 2. Ethyl 2-(3-chloro-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoate (enriched in one enantiomer) 2-(3-Chloro-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (0.50 g, 1.mmol, the mixture from Step 1) in EtOH (4.0 mL) was treated with concentrated H 2SO 4 (0.079 mL, 1.5 mmol) was added. The mixture was sealed and heated to 80 °C overnight. Upon cooling to room temperature, the reaction mixture was neutralized by the addition saturated NaHCO 3 solution. The mixture was extracted with EtOAc and the organic layer was dried over Na 2SO 4, filtered and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-15% EtOAc in hexanes to afford the product as a colorless oil (0.33 g, 42% over two steps). LCMS for C 12H 11ClF 3O 2 (M+H-H 2O)+: calculated m/z = 279.0; found 278.9.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 3. 2-(3-Chloro-4-methylphenyl)-1,1,1-trifluoro-3-methylbutane-2,3-diol (enriched in one enantiomer) Methylmagnesium bromide (3.0 M in Et 2O, 1.85 mL, 5.56 mmol) dropwise to a solution of ethyl 2-(3-chloro-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoate (0.33 g, 1.1 mmol) in THF (10 mL) at 0 °C. The mixture was then raised to ambient temperature and was stirred for 1.5 hours. Additional methylmagnesium bromide (3.0 M in Et 2O, 0.185 mL, 0.556 mmol) was added. The mixture was stirred for 30 minutes, then was cooled with an ice-water bath and quenched by the cautious addition of 1.0 N HCl. When gas evolution ceased, additional 1.0 N HCl was added to adjust to pH = 3. The mixture was stirred for 30 minutes at room temperature, then was extracted with EtOAc (2x). The combined organic extracts were dried over Na 2SO 4, filtered and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-20% EtOAc in hexanes to afford product as a colorless oil (0.22 g, 70%). LCMS for C 12H 13ClF 3O (M+H-H 2O)+: calculated m/z = 265.1; found 265.0. Step 4. 3-Amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxy-3-methylbutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide, trifluoroacetate salt (enriched in one enantiomer) The title compound was prepared by following the procedure of Example 1a, Steps 4-5, followed by the procedure of Example 17, Steps 1-3, using 2-(3-chloro-4-methylphenyl)- 1,1,1-trifluoro-3-methylbutane-2,3-diol (enriched in one enantiomer, believed to be (S)-, see stereochemical rationale supra). LCMS for C 22H 28F 3N 4O 4 (M+H)+: calculated m/z = 469.2; found 469.2. H NMR (400 MHz, MeOD) δ 8.36 – 8.30 (s, 1H), 7.80 – 7.71 (d, J = 2.0 Hz, 1H), 7.69 – 7.61 (dd, J = 7.9, 2.0 Hz, 1H), 7.36 – 7.30 (d, J = 8.1 Hz, 1H), 4.17 – 4.05 (m, 1H), 4.02 – 3.93 (dt, J = 11.8, 3.5 Hz, 2H), 3.62 – 3.51 (td, J = 11.6, 2.3 Hz, 2H), 2.46 – 2.38 (s, 3H), 1.96 – 1.85 (m, 2H), 1.75 – 1.60 (m, 2H), 1.31 – 1.28 (s, 3H), 1.28 – 1.24 (s, 3H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 23. 2-(3-(5-Amino-6-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)azetidin-3- yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (enriched in one enantiomer) Step 1. tert-Butyl 3-(3-amino-6-chloropyrazin-2-yl)azetidine-1-carboxylate Zinc dust (activated by the procedure found in WO2011/143365, the disclosure of which is incorporated herein by reference in its entirety) (0.627 g, 9.59 mmol) was charged to a dry flask and suspended in DMA (2.5 mL). 1,2-Dibromoethane (0.031 mL, 0.36 mmol) and TMSCl (0.092 mL, 0.72 mmol) were added and the reaction was stirred for 25 min. tert-Butyl 3-iodoazetidine-1-carboxylate (2.04 g, 7.20 mmol, Oakwood) in DMA (6.0 mL) was added slowly to the mixture which was immersed in a water bath to keep the temperature below ºC. The mixture was stirred for 1 hour and was degassed by bubbling a stream of nitrogen through the mixture for 5 minutes. A separate flask was charged with 3-bromo-5-chloropyrazin-2-amine (0.50 g, 2.4 mmol, D-L Chiral Chemicals), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.118 g, 0.144 mmol) and copper(I) iodide (0.057 g, 0.30 mmol). DMA (6.0 mL) was added, and the mixture was degassed by bubbling a stream of nitrogen through the mixture for 5 minutes. The solution containing the organozinc in DMA was added, excluding any remaining zinc solids. The reaction mixture was then heated at 80 ºC for 30 min. Upon cooling to room temeperature, the reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with two additional portions of EtOAc. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-100% EtOAc in hexanes to afford product (0.62 g, 90%). LCMS calculated for C 12H 18ClN 4O 2 (M+H)+: m/z = 285.1, found: 285.1. H NMR (400 MHz, CDCl 3) δ 7.96 – Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 7.90 (s, 1H), 4.78 – 4.65 (s, 2H), 4.35 – 4.22 (m, 4H), 3.79 – 3.69 (p, J = 7.4 Hz, 1H), 1.48 – 1.44 (s, 9H). Step 2. tert-Butyl 3-(3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)azetidine-1-carboxylate (enriched in one enantiomer) A degassed mixture of tert-butyl 3-(3-amino-6-chloropyrazin-2-yl)azetidine-1-carboxylate (0.615 g, 2.16 mmol), 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (0.748 g, 2.16 mmol, enriched in one enantiomer believed to be (S)-, supra), and PdCl 2(dppf)-CH 2Cl 2 adduct (0.088 g, 0.11 mmol) in dioxane (10.8 mL) and Na 2CO 3 (1.0 M in water, 6.5 mL, 6.5 mmol) was heated in a sealed vial in an oil bath held at 120 °C for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc and sufficient water to dissolve solids. The layers were separated and the aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a slow gradient from 0-100% EtOAc in hexanes (yield: 400 mg, 40%). LCMS calculated for C 22H 28F 3N 4O 4 (M+H)+: m/z = 469.2, found: 469.1. H NMR (4MHz, CDCl 3) δ 8.12 – 7.99 (s, 1H), 7.68 – 7.57 (s, 1H), 7.53 – 7.47 (d, J = 7.3 Hz, 1H), 7.– 7.33 (d, J = 8.1 Hz, 1H), 4.66 – 4.56 (s, 2H), 4.45 – 4.25 (m, 4H), 4.07 – 3.93 (m, 2H), 3.– 3.78 (m, 1H), 2.48 – 2.40 (s, 3H), 1.49 – 1.41 (s, 9H). Step 3. 2-(3-(5-Amino-6-(azetidin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane- 1,2-diol, HCl salt (enriched in one enantiomer) A solution of tert-butyl 3-(3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)azetidine-1-carboxylate (0.32 g, 0.68 mmol) was treated with HCl (1.25 M in MeOH (generated by diluting c.HCl solution with MeOH), 10.0 mL, 12.5 mmol) and the reaction was stirred at room temperature for 48 hours. Additional Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 HCl (1.25 M in MeOH, 10.0 mL, 12.5 mmol) was added and the reaction was stirred for hours. Volatiles were evaporated to afford the HCl salt, and the product was used without further purification. Step 4. 2-(3-(5-Amino-6-(1-((1-methyl-1H-pyrazol-3-yl)sulfonyl)azetidin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (enriched in one enantiomer) 2-(3-(5-Amino-6-(azetidin-3-yl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol hydrochloride salt (0.010 g, 0.025 mmol) in DCM (0.25 mL) was treated with DIPEA (0.026 mL, 0.15 mmol) and 1-methyl-1H-pyrazole-3-sulfonyl chloride (4.5 mg, 0.025 mmol, Maybridge). After 1 hour, the reaction was quenched by the addition of a small quantity of water and ammonium hydroxide solution. The mixture was concentrated via rotary evaporation to remove DCM and the mixture was diluted with MeOH and purified by preparative HPLC-MS (pH = 10) to afford the title compound (enriched in one enantiomer, believed to be (S)-, see stereochemical rationale supra) (5 mg, 40%). LCMS calculated for C 21H 24F 3N 6O 4S (M+H)+: m/z = 513.2, found: 513.1. H NMR (400 MHz, MeOD) δ 7.93 – 7.90 (s, 1H), 7.63 – 7.59 (d, J = 2.0 Hz, 1H), 7.59 – 7.55 (d, J = 8.0 Hz, 1H), 7.40 – 7.35 (m, 2H), 6.84 – 6.50 (d, J = 2.3 Hz, 1H), 4.28 – 4.24 (m, 4H), 4.14 – 4.09 (d, J = 11.8 Hz, 1H), 4.09 – 4.05 (d, J = 11.8 Hz, 1H), 4.03 – 3.94 (p, J = 8.1 Hz, 1H), 3.56 – 3.46 (s, 3H), 2.36 – 2.14 (s, 3H). F NMR (376 MHz, MeOD) δ -78.08 – -78.59 (s). Example 24. (3-(3-Amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2- yl)phenyl)pyrazin-2-yl)cyclobutyl)(3-hydroxyazetidin-1-yl)methanone trifluoroacetate salt (single enantiomer prepared) Step 1. Ethyl 3-(3-amino-6-chloropyrazin-2-yl)cyclobutane-1-carboxylate (mixture of cis and trans isomers prepared) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 A mixture of 3-bromo-5-chloropyrazin-2-amine (545 mg, 2.61 mmol, D-L Chiral Chemicals) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (178 mg, 0.261 mmol) in DMA (18.2 mL) was degassed. Separately, a vial was charged with zinc (freshly activated and dried according to the procedure found in WO2011/143365, 1.49 g, 22.8 mmol) and the vial was flushed with N and heated with a heat gun, then cooled. Dry THF (20 mL) was added. 1,2-Dibromoethane (0.20 mL, 2.4 mmol) was added and the mixture was heated with a heat gun to reflux, and then cooled to room temperature. This heating and cooling cycle was performed three times. TMSCl (0.60 mL, 4.7 mmol) was added. The mixture was heated to 50 °C in an oil bath, and ethyl 3-iodocyclobutane-1-carboxylate (2.0 g, 7.9 mmol, prepared as described in WO2014/200882, the disclosure of which is incorporated herein by reference in its entirety) in THF (10 mL) was added dropwise. The mixture was maintained at 50 °C for about 1 hour, then was cooled to room temperature and degassed by bubbling a stream of nitrogen through the mixture for 5 min. This mixture was then added to the solution of 3-bromo-5- chloropyrazin-2-amine above, excluding zinc solids. The reaction was heated to oC for 1.75 hours, then to oC for 45 minutes. Upon cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted again with EtOAc. The combined organic extracts were washed with brine, dried over Na 2SO 4, filtered, and concentrated. The product was purified via flash chromatography, eluting with a gradient from 0-75% EtOAc in hexanes to afford product (0.35 g, 52%). The cis- and trans- isomers are partially separable, however the product was carried as a mixture to the following step. LCMS calculated for C 11H 15ClN 3O 2 (M+H)+: m/z = 256.1, found: 256.0. First diastereomer to elute: 1H NMR (400 MHz, CDCl 3) δ 7.97 – 7.73 (s, 1H), 4.64 – 4.32 (s, 2H), 4.29 – 4.14 (q, J = 7.1 Hz, 2H), 3.72 – 3.52 (m, 1H), 3.27 – 3.10 (m, 1H), 2.80 – 2.51 (m, 4H), 1.35 – 1.25 (t, J = 7.1 Hz, 3H). Second diastereomer to elute: H NMR (400 MHz, CDCl 3) δ 7.98 – 7.78 (s, 1H), 4.– 4.45 (s, 2H), 4.21 – 4.12 (q, J = 7.1 Hz, 2H), 3.47 – 3.35 (p, J = 8.8 Hz, 1H), 3.26 – 3.(m, 1H), 2.77 – 2.57 (m, 4H), 1.31 – 1.25 (t, J = 7.2 Hz, 3H). 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 2. 3-(3-Amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)cyclobutane-1-carboxylic acid (two diastereomers isolated; (cis & trans); each prepared as a single enantiomer) The product of Example 1a, Step 3 (2-(3-chloro-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol ) was subjected to chiral HPLC (Phenomenex Lux Amylose-1, 21.x 250 mm, 5 μM, loading: 55 mg in 1.0 mL EtOH, eluting with 5% EtOH in hexanes at mL/min for 25 minutes). Peak 1 retention time: 19.3 min, Peak 2 retention time: 22.3 min. Peak 1 was believed to be the (S)-enantiomer (see stereochemical rationale supra), while Peak was believed to be the (R)-enantiomer. Peak 1 was collected and converted to 3,3,3- trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol according to the procedure of Example 1a, Step 4. A degassed mixture of 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol so produced (0.322 g, 0.931 mmol), ethyl 3-(3-amino-6-chloropyrazin-2-yl)cyclobutane-1-carboxylate (0.119 g, 0.465 mmol, a mixture of cis and trans isomers from Step 1) and PdCl 2(dppf)- CH 2Cl 2 adduct (0.019 g, 0.023 mmol) in dioxane (2.3 mL) and Na 2CO 3 (1.0 M in water, 1.mL, 1.4 mmol) was heated in a sealed vial held in an oil bath at 120 °C for 3 hours. Additional 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol and PdCl 2(dppf)-CH 2Cl 2 adduct (same amounts) were added as a degassed solution in dioxane (2.3 mL) and heating was continued for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with water and MeCN, filtered and purified by preparative HPLC-MS (pH = 2, Waters Xbridge C18, 30 x 100 mm, 5 uM particle size, 60 mL/min, Mobile phase A: Aq(0.1% TFA), Mobile phase B: MeCN, 16.6 - 42.2% B in min). Two diastereomers of carboxylic acid product were isolated separately. Peak 2 was subsequently used in Step 3. Peak 1 (first to elute, retention time: 5.9 min). LCMS calculated for C 19H 21F 3N 3O (M+H)+: m/z = 412.1, found: 412.3. Peak 2 (second to elute, retention time: 6.7 min). LCMS calculated for C 19H 21F 3N 3O (M+H)+: m/z = 412.1, found: 412.3. Peak 2 was used in Step 3. Step 3. (3-(3-Amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin- 2-yl)cyclobutyl)(3-hydroxyazetidin-1-yl)methanone (single enantiomer prepared) Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 To 3-(3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazin-2-yl)cyclobutane-1-carboxylic acid (0.011 g, 0.027 mmol, from Peak 2 of Step 2), azetidin-3-ol hydrochloride (3.6 mg, 0.053 mmol, Oakwood) and DIPEA (0.023 mL, 0.13 mmol) in DMF (1.0 mL) was added HATU (0.015 g, 0.040 mmol). The reaction was stirred for 30 minutes, diluted with MeOH and purified by preparative HPLC-MS (pH = 2). The product is believed to be the (S)-configuration at the tertiary alcohol, supra). LCMS calculated for C 22H 26F 3N 4O 4 (M+H)+: m/z = 467.2, found: 467.1. H NMR (400 MHz, MeOD) δ 7.90 – 7.82 (s, 1H), 7.75 – 7.66 (s, 1H), 7.62 – 7.52 (d, J = 8.2 Hz, 1H), 7.41 – 7.(d, J = 8.1 Hz, 1H), 4.63 – 4.53 (m, 1H), 4.39 – 4.31 (m, 1H), 4.29 – 4.19 (m, 1H), 4.14 – 4.06 (d, J = 11.8 Hz, 1H), 4.06 – 3.98 (d, J = 11.8 Hz, 1H), 3.95 – 3.84 (m, 1H), 3.84 – 3.71 (m, 2H), 2.75 – 2.62 (m, 4H), 2.50 – 2.46 (s, 3H). F NMR (376 MHz, MeOD) δ -77.26 – -77.60 (s), -78.10 – -78.35 (s). Example 25. 2-(3-(5-Amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3- trifluoropropane-1,2-diol (single enantiomer prepared) Step 1. 5-Bromo-3-(trifluoromethyl)pyrazin-2-amine To 3-(trifluoromethyl)pyrazin-2-amine (0.020 g, 0.12 mmol, Oakwood) in CH 2Cl (0.5 mL) was added N-bromosuccinimide (0.022 g, 0.12 mmol) and the reaction was stirred overnight. The reaction mixture was partitioned between DCM and water, and the aqueous portion was extracted with three portions of DCM. The combined organic extracts were dried over Na 2SO 4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-25% EtOAc in hexanes to afford a white crystalline solid (0.013 g, 44%). H NMR (400 MHz, CDCl 3) δ 8.44 – 8.23 (s, 1H), 5.22 – 4.98 (s, 2H). F NMR (376 MHz, CDCl 3) δ -65.04 – -69.69 (s). Step 2. 2-(3-(5-Amino-6-(trifluoromethyl)pyrazin-2-yl)-4-methylphenyl)-3,3,3-trifluoropropane-1,2-diol (single enantiomer prepared) A degassed mixture of 5-bromo-3-(trifluoromethyl)pyrazin-2-amine (0.030 g, 0.mmol, prepared as in Step 1), 3,3,3-trifluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 dioxaborolan-2-yl)phenyl)propane-1,2-diol (0.043 g, 0.124 mmol, single enantiomer obtained as described in Example 24, Step 2) and PdCl 2(dppf)-CH 2Cl 2 adduct (5.0 mg, 6.2 μmol) in dioxane (0.6 mL) and Na 2CO 3, (1.0 M in water, 0.37 mL, 0.37 mmol) was heated in a sealed vial in an oil bath held at 120 °C for 3 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc and water sufficient to dissolve solids. The layers were separated and the aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were dried over Na 2SO 4, filtered and concentrated. The product was purified by preparative HPLC-MS (pH = 10). The product is believed to be the (S)-configuration at the tertiary alcohol, (see stereochemical rationale supra)). LCMS for C 15H 14F 6N 3O 2 (M+H)+: m/z = 382.1, found: 382.1. H NMR (400 MHz, CDCl 3) δ 8.43 – 8.37 (s, 1H), 7.68 – 7.57 (s, 1H), 7.53 – 7.44 (d, J = 7.9 Hz, 1H), 7.42 – 7.32 (d, J = 8.1 Hz, 1H), 5.19 – 5.08 (s, 2H), 4.38 – 4.28 (d, J = 11.8 Hz, 1H), 3.99 – 3.91 (d, J = 11.9 Hz, 1H), 3.85 – 3.63 (br s, 1H), 2.49 – 2.30 (s, 3H). F NMR (376 MHz, CDCl 3) δ -65.20 – -70.41 (s), -74.– -80.34 (s). Examples 26-37.Compounds in Table 4 were prepared by the method of Example 17, using the appropriate amines instead of tetrahydro-2H-pyran-4-amine in Step 3. Where the compound was isolated as the TFA salt, preparative HPLC-MS (pH = 2) conditions were used for purification. Where the compound was isolated as the free base, preparative HPLC-MS (pH = 10) conditions were used for purification. Table 4.
Example No. Compound Name R LCMS H NMR 26 3-Amino-N-((1s,3R)-3-cyanocyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 20H 18D 3F 3N 5O 3 (M+H)+: m/z = 439.2, found: 439.4 H NMR (500 MHz, DMSO-d 6) δ 8.99 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 7.89 – 7.25 (br s, 2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 4.49 (h, J = 8.6 Hz, 1H), 3.94 (s, 2H), 3.05 (tt, J = 10.0, 8.1 Hz, 1H), 2.62 – 2.53 (m, 4H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example No. Compound Name R LCMS H NMR 27 3-Amino-N-((1S,2S)-2-hydroxycyclohexyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 21H 23D 3F 3N 4O 4 (M+H)+: m/z = 458.2, found: 458.1 H NMR (400 MHz, CD 3OD) δ 8.32 (d, J = 0.9 Hz, 1H), 7.69 (d, J = 1.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 8.1, 1.0 Hz, 1H), 4.09 (d, J = 11.8 Hz, 1H), 4.02 (d, J = 11.8 Hz, 1H), 3.74 (td, J = 9.8, 4.1 Hz, 1H), 3.49 (td, J = 9.8, 4.2 Hz, 1H), 2.15 – 1.98 (m, 2H), 1.86 – 1.61 (m, 2H), 1.53 – 1.23 (m, 4H). 28 3-Amino-N-((trans)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide (single enantiomer) Calculated for C 20H 21D 3F 3N 4O 5 (M+H)+: m/z = 460.2, found: 460.1 H NMR (500 MHz, DMSO-d 6) δ 8.38 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.73 – 7.52 (br s, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.1, 2.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 5.17 (t, J = 5.8 Hz, 1H), 4.99 (d, J = 5.7 Hz, 1H), 3.– 3.88 (m, 2H), 3.85 – 3.74 (m, 3H), 3.56 – 3.48 (m, 1H), 3.37 – 3.33 (m, 1H), 3.04 (dd, J = 11.1, 9.8 Hz, 1H), 1.92 – 1.83 (m, 1H), 1.66 – 1.54 (m, 1H). 29 3-Amino-N-((1s,3R)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 20H 18D 3F 6N 4O 4 (M+H)+: m/z = 498.2, found: 498.1H NMR (600 MHz, DMSO-d 6) δ 8.84 (d, J = 7.9 Hz, 1H), 8.36 (s, 1H), 7.74 – 7.49 (br s, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 6.46 (s, 1H), 5.19 (t, J = 5.3 Hz, 1H), 4.22 – 4.12 (m, 1H), 3.98 – 3.89 (m, 2H), 2.82 – 2.70 (m, 2H), 2.45 – 2.33 (m, 2H). 3-Amino-N-((1s,3R)-3-hydroxy-1-methylcyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 20H 21D 3F 3N 4O 4 (M+H)+: m/z = 444.2, found: 444.1H NMR (400 MHz, CD 3OD) δ 8.32 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 7.9, 1.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 4.17 (p, J = 7.2 Hz, 1H), 4.09 (d, J = 11.8 Hz, 1H), 4.02 (d, J = 11.7 Hz, 1H), 2.67 – 2.55 (m, 2H), 2.33 – 2.18 (m, 2H), 1.49 (s, 3H). 31 (S)-3-Amino-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide (single enantiomer) Calculated for C 22H 23D 3F 3N 4O 4 (M+H)+: m/z = 470.2, found: 470.1 H NMR (500 MHz, DMSO-d 6) δ 8.62 (s, 1H), 8.37 (s, 1H), 7.69 – 7.54 (br s, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 5.16 (t, J = 5.8 Hz, 1H), 4.46 (t, J = 5.5 Hz, 1H), 3.97 – 3.(m, 2H), 3.49 (d, J = 5.4 Hz, 2H), 1.94 – 1.85 (m, 2H), 1.81 – 1.74 (m, 2H), 1.55 – 1.49 (m, 2H), 1.49 – 1.41 (m, 2H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example No. Compound Name R LCMS H NMR 32 (S)-3-Amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide (single enantiomer) Calculated for C 21H 21D 3F 3N 4O 4 (M+H)+: m/z = 456.2, found: 456.1 H NMR (500 MHz, DMSO-d 6) δ 8.86 (s, 1H), 8.34 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 5.17 (t, J = 5.8 Hz, 1H), 4.51 (t, J = 5.6 Hz, 1H), 3.93 (d, J = 5.8 Hz, 2H), 3.48 (d, J = 5.Hz, 2H), 1.95 (s, 6H). 33 3-Amino-N-((S)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 18H 19D 3F 3N 4O 4 (M+H)+: m/z = 418.2, found: 418.3 34 (S)-3-Amino-N-(2-cyano-2-methylpropyl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide (single enantiomer) Calculated for C 20H 20D 3F 3N 5O 3 (M+H)+: m/z = 441.2 , found: 441.1 H NMR (500 MHz, DMSO-d 6) δ 8.76 (t, J = 6.8 Hz, 1H), 8.43 (s, 1H), 7.68 – 7.54 (br s, 2H), 7.64 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.1, 1.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 6.43 (br s, 1H), 5.17 (br s, 1H), 3.94 (s, 2H), 3.50 (d, J = 6.8 Hz, 2H), 1.33 (s, 6H).
(S)-3-Amino-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 22H 23D 3F 3N 4O 4 (M+H)+: m/z = 470.2, found: 470.1 36 3-Amino-N-((R)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 18H 19D 3F 3N 4O 4 (M+H)+: m/z = 418.2, found: 418.3 H NMR (500 MHz, DMSO-d 6) δ 8.39 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.89 – 7.40 (br s, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.55 – 7.50 (m, 1H), 7.34 (d, J = 8.0 Hz, 1H), 4.04 – 3.96 (m, 1H), 3.96 – 3.85 (m, 2H), 3.51 – 3.36 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H). 37 (S)-3-Amino-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 21H 21D 3F 3N 4O 4 (M+H)+: m/z = 456.2, found: 456.1 H NMR (500 MHz, DMSO-d 6) δ 8.59 (s, 1H), 8.37 (s, 1H), 7.79 – 7.45 (br s, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 7.8, 1.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 5.69 (s, 1H), 5.19 (t, J = 5.9 Hz, 1H), 4.03 – 3.83 (m, 2H), 1.– 1.83 (m, 2H), 1.83 – 1.80 (m, 2H), 1.80 – 1.75 (m, 2H), 1.63 – 1.56 (m, 2H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 The amine required for synthesis of Example 37 was prepared as described in WO2017/223414, the disclosure of which is incorporated herein by reference in its entirety. Compounds in Table 5 were prepared by the method of Example 18, using the appropriate amines instead of 4-aminobicyclo[2.2.1]heptan-1-ol in Step 9. Where the compound was isolated as the TFA salt, preparative HPLC-MS (pH = 2) conditions were used for purification. Where the compound was isolated as the free base, preparative HPLC-MS (pH = 10) conditions were used for purification. Table 5.
Example No. Compound Name R LCMS H NMR 38 3-Amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1S,2S)-2-hydroxycyclohexyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 21H 24D 3F 2N 4O (M+H)+: m/z = 440.2, found: 440.2 H NMR (400 MHz, DMSO-d 6) δ 8.38 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.(d, J = 1.9 Hz, 1H), 7.46 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.6 Hz, 1H), 3.78 (d, J = 10.7 Hz, 1H), 3.69 (d, J = 10.6 Hz, 1H), 3.62 – 3.48 (m, 2H), 1.99 – 1.80 (m, 2H), 1.69 – 1.54 (m, 2H), 1.35 – 1.10 (m, 4H). F{H} NMR (376 MHz, DMSO-d 6) δ -74.05 (s), -129.75 (d, J F-F = 277.6 Hz), -134.32 (d, J F-F = 277.2 Hz). 39 3-Amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 21H 24D 3F 2N 4O (M+H)+: m/z = 440.2, found: 440.1H NMR (400 MHz, DMSO-d 6) δ 8.38 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.(d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.6 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 11.0 Hz, 1H), 3.61 – 3.50 (m, 1H), 3.47 – 3.30 (m, 1H), 2.01 – 1.80 (m, 2H), 1.71 – 1.52 (m, 2H), 1.37 – 1.12 (m, 4H). F{H} NMR (376 MHz, DMSO-d 6) δ -74.45 (s), -129.80 (d, J F-F = 277.4 Hz), -134.32 (d, J F-F = 277.4 Hz).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 40. (S)-3-Amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3- dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxamide (single enantiomer prepared) Step 1. tert-Butyl (4-carbamoylbicyclo[2.1.1]hexan-1-yl)carbamate A solution of 4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid (250 mg, 1.0 mmol) (Spirochem catalog # SPC-a643) and triethylamine (0.17 mL, 1.2 mmol) in THF (5.0 mL) at -15 °C was treated with ethyl chloroformate (0.11 mL, 1.1 mmol) and the reaction was stirred for 1 hour. To the mixture was added ammonium hydroxide (15 M, 7.mL, 52 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were dried over Na 2SO 4, filtered and concentrated to afford the title compound as a white solid (220 mg, 88%). LCMS for C 12H 21N 2O 3 (M+H)+: calculated m/z = 241.2, found 241.3. H NMR (400 MHz, DMSO-d 6) δ 7.30 (br s, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 1.93 (br, 2H), 1.70 (s, 4H), 1.49 (s, 2H), 1.38 (s, 9H). Step 2. tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate Trichloroacetyl chloride (0.54 mL, 4.8 mmol) was added to a solution of tert-butyl (4-carbamoylbicyclo[2.1.1]hexan-1-yl)carbamate (290 mg, 1.2 mmol, prepared according to the method of Step 1) and triethylamine (1.4 mL, 9.7 mmol) in DCM (20 mL) at 0 °C. After minutes, the reaction was quenched by the addition of saturated NaHCO 3 solution, and the aqueous mixture was extracted with DCM. The organic extract was dried over MgSO 4, 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 filtered, and concentrated. The product was purified by flash column chromatography (eluting with a gradient of 0-20% EtOAc/hexanes) to afford the title compound as a white solid (2mg, 86%). LCMS for C 12H 19N 2O 2 (M+H)+: calculated m/z = 223.1, found 223.1. H NMR (400 MHz, CD 3OD) δ 2.35 (br, 2H), 2.06 – 1.98 (m, 2H), 1.90 – 1.82 (m, 2H), 1.82 – 1.(m, 2H), 1.45 (s, 9H). Step 3. 4-Aminobicyclo[2.1.1]hexane-1-carbonitrile, hydrochloric acid salt tert-Butyl (4-cyanobicyclo[2.1.1]hexan-1-yl)carbamate (0.99 g, 4.5 mmol, prepared by the method of Step 2) was dissolved in DCM (50 mL) and HCl in dioxane (4.0 M, 11 mL, mmol) was added. The mixture was stirred overnight and volatiles were removed in vacuo to afford the title compound as a white solid (0.7 g, 100%). LCMS for C 7H 11N 2 (M+H)+: calculated m/z = 123.1, found 123.2. H NMR (500 MHz, DMSO-d 6) δ 9.03 (s, 3H), 2.26 – 2.20 (m, 2H), 2.11 – 2.06 (m, 2H), 1.89 – 1.82 (m, 4H). Step 4. 3-Amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxamide (single enantiomer prepared) To a solution of 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxylic acid (believed to be the (S)- enantiomer, 50 mg, 0.15 mmol, from Example 18, Step 8) in DMF (1.5 mL) was added HATU (72 mg, 0.19 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.58 mmol). To this mixture was added 4- aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (28 mg, 0.18 mmol), and the reaction mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc and the organic mixture was washed with water (2x). The combined aqueous layers were extracted with EtOAc (2x) and combined with the initial organic extract. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified via preparative HPLC-MS (pH 10) to afford the title compound (22 mg, 34%). The product is believed to be the (S)-enantiomer (see stereochemical rationale vide supra). LCMS for C 22H 21D 3F 2N 5O 3 (M+H)+: m/z = 447.2, found: 447.1. H NMR (500 MHz, DMSO-d 6) δ 8.93 (s, 1H), 8.36 (s, 1H), 7.66 – 7.50 (br s, 2H), 7.55 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 8.0, 1.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.20 (t, J = 55.6 Hz, 1H), 5.81 (s, 1H), 5.09 (t, J = 6.0 Hz, 1H), 3.78 (dd, J = 11.8, 5.9 Hz, 1H), 3.69 (dd, J = 11.5, 5.5 Hz, 1H), 2.38 – 2.30 (m, 2H), 2.08 – 1.99 (m, 2H), 1.99 – 1.96 (m, 2H), 1.96 – 1.90 (m, 2H).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 41. (S)-3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl- d 3)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (single enantiomer prepared) Carbon monoxide was bubbled through a mixture of (S)-2-(3-(5-amino-6- chloropyrazin-2-yl)-4-(methyl-d 3)phenyl)-3,3-difluoropropane-1,2-diol (160 mg, 0.48 mmol, Peak 1 from Example 18, Step 7 believed to be the (S)-enantiomer), tetrahydro-2H-pyran-4-amine (0.40 mL, 3.9 mmol, Combi-Blocks #AM-1004), triethylamine (0.54 mL, 3.9 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (mg, 0.096 mmol) in dioxane (9.6 mL) for 5 minutes. The reaction was heated at 90 °C under 1 atm of CO overnight. The volatiles were removed in vacuo, and the residue was diluted with EtOAc and saturated NH 4Cl solution. After stirring for 15 minutes, the biphasic mixture was filtered through Celite®, and the layers of the filtrate were separated. The aqueous layer was extracted with EtOAc (2x). The combined organic extracts were dried over Na 2SO 4, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-100% in EtOAc in hexanes, afforded the desired product. The product was further purified via preparative HPLC-MS (pH = 10) to afford the title compound (0.13 g, 63%). The product is believed to be the (S)-enantiomer (see stereochemcial rationale supra). LCMS for C 20H 22D 3F 2N 4O (M+H)+: m/z = 426.2, found: 426.2. H NMR (500 MHz, DMSO-d 6) δ 8.38 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 7.71 – 7.52 (br s, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.5 Hz, 1H), 5.82 (s, 1H), 5.09 (s, 1H), 4.06 – 3.95 (m, 1H), 3.85 (dt, J = 11.4, 3.5 Hz, 2H), 3.78 (d, J = 11.2 Hz, 1H), 3.69 (d, J = 11.1 Hz, 1H), 3.(td, J = 11.6, 2.3 Hz, 2H), 1.77 – 1.71 (m, 2H), 1.64 (qd, J = 12.5, 11.9, 4.4 Hz, 2H). 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 42. (S)-3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2- methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (single enantiomer prepared) Step 1. 1-(3-Chloro-4-methylphenyl)-2,2-difluoroethan-1-one 1,2-Dibromoethane (2 drops) was added to a vigorously-stirred mixture of Mg powder (1.2 g, 0.050 mol) in THF (40.0 mL) in a flask that was immersed in a room temperature water bath. After 10 minutes, 4-bromo-2-chloro-1-methylbenzene (8.9 g, mmol, Aldrich 528889) in THF (30 mL) was added dropwise. After complete addition, two more drops of 1,2-dibromoethane were added. After stirring for 2 h, the reaction mixture was cooled to 0 °C, stirred for 5 min, and a solution of 2,2-difluoro-N-methoxy-N-methylacetamide (5.0 g, 36 mmol, Oakwood 034757) in THF (20 mL) was then added dropwise. The reaction mixture was stirred for 10 min at 0 °C. The ice bath was removed, and the mixture was allowed to warm to room temperature. The reaction was carefully quenched by the addition of 2.0 N HCl (170 mL), and the reaction mixture was stirred for 15 min. The layers of the mixture were separated. The aqueous layer was extracted with MTBE (3 x 1mL). The combined organic extracts were washed successively with 1.0 N HCl, water, and brine. The organic layer was dried over Na 2SO 4, filtered and concentrated. Purification via flash chromatography, eluting with a gradient from 0-5% EtOAc in hexanes, afforded the title compound (7.0 g, 95%). H NMR (400 MHz, CDCl 3) δ 8.09 – 8.04 (m, 1H), 7.93 – 7.84 (m, 1H), 7.42 (d, J = 7.9 Hz, 1H), 6.26 (t, J = 53.5 Hz, 1H), 2.50 (s, 3H). F{H} NMR (3MHz, CDCl 3) δ -121.72 (s).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 2. 2-Chloro-4-(3,3-difluoroprop-1-en-2-yl)-1-methylbenzene To a solution of tris(triphenylphosphine)rhodium(I) chloride (2.4 g, 2.6 mmol) and triphenylphosphine (14 g, 55 mmol) in THF (140 mL) under N 2, was added dry 2-propanol (4.2 mL, 55 mmol), followed by a solution of 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan- 1-one (7.0 g, 34 mmol) in THF (42 mL). Trimethylsilyldiazomethane (2.0 M in ether, 34 mL, mmol) was added to the mixture, and the reaction was stirred at ambient temperature for 1.5 h. The reaction mixture was quenched by the dropwise addition of acetic acid (3.9 mL, mmol), and the mixture was stirred for 30 min. Volatiles were removed in vacuo. Purification via flash chromatography, eluting with 100% hexanes, afforded the title compound (3.8 g, 55%). H NMR (400 MHz, CDCl 3) δ 7.49 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 7.7, 1.5 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.38 (t, J = 55.2 Hz, 1H), 5.74 (t, J = 1.9 Hz, 1H), 5.68 (t, J = 2.Hz, 1H), 2.41 (s, 3H). F{H} NMR (376 MHz, CDCl 3) δ -113.20 (s). Step 3. 2-(3-Chloro-4-methylphenyl)-3,3-difluoropropane-1,2-diol (enriched in one enantiomer) To a suspension of AD-mix-alpha (26.3 g, 56.3 mmol) in water (50.0 mL) at 0 °C was added a solution of 2-chloro-4-(3,3-difluoroprop-1-en-2-yl)-1-methylbenzene (3.80 g, 18.8 mmol) in t-BuOH (50.0 mL). The reaction was stirred at 3-6 ºC for 40 h. The reaction was quenched by the addition of sodium sulfite (8 g). The reaction was stirred for 10 min, then was concentrated via rotary evaporation to remove t-BuOH. The aqueous mixture was diluted with water and extracted with EtOAc (3x). The combined organic extracts were dried over Na 2SO 4, filtered and concentrated. The product was purified via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, to afford the title compound (3.82 g, 86%). The product is believed to be enriched in the (S)- isomer (see stereochemical rationale supra). H NMR (400 MHz, CDCl 3) δ 7.56 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.1, 1.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 5.91 (t, J = 55.8 Hz, 1H), 4.19 (ddd, J = 11.6, 6.4, 1.3 Hz, 1H), 3.91 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 – 3.75 (m, 1H), 3.29 (s, 1H), 2.40 (s, 3H), 1.88 (t, J = 6.3 Hz, 1H). F{H} NMR (376 MHz, CDCl 3) δ -128.20 (d, J F-F = 284.4 Hz), -132.44 (d, J F-F = 284.3 Hz). Step 4. 3,3-Difluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (enriched in one enantiomer) A mixture of 2-(3-chloro-4-methylphenyl)-3,3-difluoropropane-1,2-diol (from Step 3, believed to be enriched in the (S)- enantiomer, 2.4 g, 10. mmol), bis(pinacolato)diboron (7.g, 30. mmol), potassium acetate (6.0 g, 61 mmol), Pd 2(dba) 3 (0.46 g, 0.51 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.97 g, 2.0 mmol) in dioxane (mL) was degassed by sparging with N 2 for 5 min. The reaction mixture was heated in a sealed vial at 120 °C for 3.5 h. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite®, and concentrated under rotary evaporation. Purification via flash chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, afforded the title compound (4.0 g, theoretical yield assumed). LCMS for C 16H 27BF 2NO 4 (M+NH 4)+: m/z = 346.2, found: 346.2. Step 5. 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3-difluoropropane-1,2-diol (single enantiomer isolated, believed to be the (S)- isomer) A mixture of 5-bromo-3-chloropyrazin-2-amine (2.3 g, 11 mmol), and 3,3-difluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (from Step 4, believed to be enriched in the (S)- enantiomer, 3.3 g, 10. mmol) in dioxane (100 mL) was degassed by sparging with N 2 for 5 min. To the reaction mixture was was added Na 2CO solution (30. mL, 30. mmol) and PdCl 2(dppf)-CH 2Cl 2 adduct (0.41 g, 0.51 mmol), and the mixture was degassed by sparging with N 2 for 2 min. The reaction mixture was heated at 1°C for 3 h. Upon cooling, the reaction mixture was partitioned between water and EtOAc, and the biphasic mixture was filtered through Celite®. The layers were separated, and the aqueous Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 layer was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated. Purification via flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes, afforded the title compound (1.3 g, 38% yield over two steps). The enantiomers were separated via chiral HPLC (Phenomenex Lux Amylose-1, 21.2 x 250 mm, 5 μM, loading: 90 mg in 1.4 mL EtOH, eluting with 45% EtOH in hexanes at 20 mL/min). Peak 1 retention time: 8.2 min, Peak 2 retention time: 13.2 min. Peak 1 was the major enantiomer and was believed to be the (S)- enantiomer (see stereochemical rationale supra) and was used in Step 6 (0.80 g). LCMS for C 14H 15ClF 2N 3O (M+H)+: m/z = 330.1, found: 330.0. H NMR (500 MHz, DMSO-d 6) δ 8.12 (s, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 7.9, 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.88 (s, 2H), 6.19 (t, J = 55.6 Hz, 1H), 5.81 (s, 1H), 5.07 (t, J = 5.5 Hz, 1H), 3.79 – 3.73 (m, 1H), 3.70 – 3.62 (m, 1H), 2.33 (s, 3H). Step 6. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylic acid (single enantiomer prepared) Triethylamine (0.17 mL, 1.2 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (25 mg, 0.031 mmol) were added to a solution of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3-difluoropropane-1,2-diol (Peak 1 from Step 5, believed to be the (S)-enantiomer, 0.10 g, 0.mmol) in ethanol (6.0 mL). Carbon monoxide was bubbled through the solution for 10 min. The reaction mixture was heated at 80 °C under 1 atm of CO for 1.5 h. Volatiles were removed in vacuo. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes, afforded ethyl 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylate (0.10 g). LCMS for C 17H 20F 2N 3O 4 (M+H)+: m/z = 368.1, found: 368.1. A solution of ethyl 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylate (0.10 g, 0.28 mmol) in MeOH (2.0 mL) was treated with a solution of LiOH (37 mg, 1.5 mmol) in water (2.0 mL). The mixture was stirred for min, and MeOH was removed in vacuo. The aqueous mixture was acidified to pH = 3 by the addition of 1.0 N HCl, saturated with NaCl, and extracted with EtOAc (4x). The combined organic extracts were dried over Na 2SO 4, filtered and concentrated to afford the title Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 compound, which was used without further purification (91 mg, 87%). LCMS for C 15H 16F 2N 3O 4 (M+H)+: m/z = 340.1, found: 340.1. Step 7. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (single enantiomer prepared) To a solution of 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2- methylphenyl)pyrazine-2-carboxylic acid (from Step 6, believed to be the (S)- enantiomer, mg, 0.17 mmol) in DMF (2.0 mL) was added HATU (84 mg, 0.22 mmol), diisopropylethylamine (0.090 mL, 0.51 mmol), and tetrahydro-2H-pyran-4-amine (21 mg, 0.21 mmol, Combi-Blocks #AM-1004). The reaction mixture was stirred for 30 min, was diluted with EtOAc, and washed twice with water. The aqueous layers were combined and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over Na 2SO 4, filtered and concentrated. Flash chromatography, eluting with a gradient of 0-100% EtOAc on hexanes, afforded 80 mg of oil. The oil was purifed via preparative HPLC-MS (pH = 10) and lyophilized to afford the title compound as a white powder (36 mg, 50%). The product is believed to be the (S)- enantiomer (see stereochemical rationale supra). LCMS for C 20H 25F 2N 4O 4 (M+H)+: m/z = 423.2, found: 423.2. H NMR (500 MHz, DMSO-d 6) δ 8.(s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.71 – 7.50 (br s, 2H), 7.58 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 7.8, 2.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.6 Hz, 1H), 5.82 (s, 1H), 5.09 (s, 1H), 4.06 – 3.95 (m, 1H), 3.90 – 3.81 (m, 2H), 3.78 (d, J = 11.2 Hz, 1H), 3.69 (d, J = 11.1 Hz, 1H), 3.44 – 3.37 (m, 2H), 2.36 (s, 3H), 1.79 – 1.70 (m, 2H), 1.64 (qd, J = 11.4, 4.3 Hz, 2H). Compounds in Table 6 were prepared by the method of Example 42, using the appropriate amines instead of tetrahydro-2H-pyran-4-amine in Step 7. Where the compound was isolated as the TFA salt, preparative HPLC-MS (pH = 2) conditions were used for purification. Where the compound was isolated as the free base, preparative HPLC-MS (pH = 10) conditions were used for purification. 25 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Table 6.
Example No. Compound Name R LCMS H NMR 43 3-Amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-((S)-1-hydroxypropan-2-yl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 18H 23F 2N 4O (M+H)+: m/z = 397.2, found: 397.1 H NMR (400 MHz, DMSO-d 6) δ 8.38 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.80 – 7.49 (br s, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.1, 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.5 Hz, 1H), 4.06 – 3.95 (m, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.69 (d, J = 11.1 Hz, 1H), 3.48 – 3.36 (m, 2H), 2.35 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H). 44 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 22H 27F 2N 4O (M+H)+: m/z = 449.2, found: 449.1 H NMR (400 MHz, DMSO-d 6) δ 8.40 (s, 1H), 8.21 (s, 1H), 7.72 – 7.48 (br s, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 7.9, 2.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.(t, J = 55.5 Hz, 1H), 3.82 – 3.73 (m, 1H), 3.73 – 3.65 (m, 1H), 2.36 (s, 3H), 2.09 – 1.(m, 2H), 1.93 – 1.79 (m, 4H), 1.78 – 1.63 (m, 2H), 1.63 – 1.39 (m, 2H). 45 (3-Amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazin-2-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone, trifluoroacetate salt (single enantiomer) Calculated for C 20H 25F 2N 4O (M+H)+: m/z = 423.2, found: 423. 46 (S)-3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-isopropylpyrazine-2-carboxamide, trifluoroacetate salt (single enantiomer) Calculated for C 18H 23F 2N 4O (M+H)+: m/z = 381.2, found: 381.1H NMR (400 MHz, DMSO-d 6) δ 8.37 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.78 – 7.40 (br s, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 7.9, 1.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.21 (t, J = 55.6 Hz, 1H), 4.16 – 4.00 (m, 1H), 3.78 (dd, J = 11.3, 2.2 Hz, 1H), 3.69 (dd, J = 11.2, 2.0 Hz, 1H), 2.35 (s, 3H), 1.18 (d, J = 6.6 Hz, 6H). 47 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(3-methyltetrahydrofuran-3-yl)pyrazine-2-carboxamide, trifluoroacetate salt (mixture of two diastereomers) Calculated for C 20H 25F 2N 4O (M+H)+: m/z = 423.2, found: 423.
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Example 48. 3-Amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3- dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide (single enantiomer prepared) Step 1. 2-(3-Chloro-4-methylphenyl)-1,1-difluoro-3-(trimethylsilyl)propan-2-ol A solution of ((trimethylsilyl)methyl)magnesium chloride (1.0 M in Et 2O, 67 mL, mmol, Aldrich) was added dropwise to 1-(3-chloro-4-methylphenyl)-2,2-difluoroethan-1-one (9.1 g, 45 mmol, prepared as in Example 42, Step 1) in diethyl ether (56 ml) at 0 °C. After complete addition of the organomagnesium solution, the mixture was stirred for 10 minutes at 0 °C, then the reaction mixture was allowed to warm to ambient temperature and was stirred for 1.5 hours. The reaction mixture was cooled to 0 °C and was quenched by the dropwise addition of aq. HCl solution (2.0 N, 36 mL, 72 mmol). The mixture was warmed to room temperature and was diluted with water (100 mL) and extracted with MTBE (100 mL). The aqueous layer was separated and was extracted again with MTBE (3 x 50 mL). The combined organic extracts were washed successively with 2.0 N HCl, water, and brine, then dried over sodium sulfate, filtered and concentrated. The product was used without further purification (13 g, 99%). H NMR (400 MHz, CDCl 3) δ 7.48 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 8.1, 1.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 5.56 (t, J = 57.1 Hz, 1H), 2.37 (s, 3H), 1.40 (dt, J = 15.0, 1.Hz, 1H), 1.32 (d, J = 15.1 Hz, 1H), -0.14 (s, 9H). Step 2. 2-Chloro-4-(3,3-difluoroprop-1-en-2-yl)-1-methylbenzene Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Trimethylsilyl trifluoromethanesulfonate (1.2 mL, 6.7 mmol) was added dropwise to a solution of 2-(3-chloro-4-methylphenyl)-1,1-difluoro-3-(trimethylsilyl)propan-2-ol (13 g, mmol) in DCM (220 mL) at 0 °C. The mixture was stirred for 10 minutes at 0 °C, then was allowed to warm to ambient temperature and was stirred for 1.5 hours. The reaction flask was immersed in a water bath and saturated NaHCO 3 solution (120 mL) was introduced. The mixture was extracted with MTBE (180 mL). The aqueous layer was separated and extracted with additional MTBE (3 x 60 mL). The combined organic extracts were washed successively with saturated NaHCO 3 solution (120 mL), water (120 mL), and brine (140 mL), dried over Na 2SO 4, filtered and concentrated. The product was purified via flash column chromatography, eluting with 100% hexanes to afford the title compound (8.3 g, 92%). H NMR (400 MHz, CDCl 3) δ 7.47 (d, J = 1.7 Hz, 1H), 7.28 (dd, J = 8.1, 1.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.35 (t, J = 55.2 Hz, 1H), 5.72 (t, J = 1.9 Hz, 1H), 5.66 (t, J = 2.3 Hz, 1H), 2.39 (s, 3H). F{H} NMR (376 MHz, CDCl 3) δ -113.19 (s). Step 3. 2-(3-Chloro-4-methylphenyl)-3,3-difluoropropane-1,2-diol (enriched in one enantiomer) A solution of 2-chloro-4-(3,3-difluoroprop-1-en-2-yl)-1-methylbenzene (4.8 g, mmol) in tert-butanol (64 mL) was added to a suspension of AD-mix-α (33 g, 72 mmol, Aldrich #392758) in water (63 mL) at 0 °C. The mixture was then stirred at 3 °C for 3 days. Sodium sulfite (10 g) was added, and the resulting mixture was stirred for 10 minutes. Solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc. The combined extracts were dried over Na 2SO 4, filtered and concentrated. Flash column chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, afforded the title compound (5.0 g, 89%). The product is believed to be enriched in the (S)- isomer (see stereochemical rationale vide supra). H NMR (400 MHz, CDCl 3) δ 7.56 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.1, 1.7 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.91 (t, J = 55.8 Hz, 1H), 4.22 – 4.(m, 1H), 3.88 – 3.81 (m, 1H), 3.31 (s, 1H), 2.40 (s, 3H), 1.92 (t, J = 6.4 Hz, 1H). F{H} NMR (376 MHz, CDCl 3) δ -128.19 (d, J = 284.2 Hz), -132.47 (d, J F-F = 284.2 Hz). 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Step 4. 3,3-Difluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (enriched in one enantiomer) A degassed mixture of 2-(3-chloro-4-methylphenyl)-3,3-difluoropropane-1,2-diol (from Step 3, believed to be enriched in the (S)- enantiomer, 2.4 g, 10 mmol), bis(pinacolato)diboron (7.7 g, 30 mmol), potassium acetate (6.0 g, 61 mmol), Pd 2(dba) 3 (0.g, 0.51 mmol) and 2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl (0.97 g, 2.mmol) in dioxane (80 mL) was heated in a sealed vial at 120 °C for 3.5 hours. Upon cooling, the reaction mixture was diluted with EtOAc, filtered through Celite®, and concentrated. The product was purified via flash column chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, to afford the title compound which was used without further purification in Step 5. Theoretical yield was assumed. LCMS for C 16H 27BF 2NO 4 (M+NH 4)+: m/z = 346.2, found: 346.2. Step 5. 2-(3-(5-Amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3-difluoropropane-1,2-diol (single enantiomer isolated, believed to be the (S)- isomer) To a flask equipped with reflux condenser was added 5-bromo-3-chloropyrazin-2-amine (2.3 g, 11 mmol, Ark Pharm #AK-25099), 3,3-difluoro-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane-1,2-diol (from Step 4, believed to be enriched in the (S)-enantiomer, 3.3 g, 10 mmol), and dioxane (100 mL). Sodium carbonate solution (30 mL, 30 mmol) and PdCl 2(dppf)-CH 2Cl 2 adduct (0.41 g, 0.51 mmol) were introduced, and the mixture was sparged with N 2 for 2 minutes. The reaction mixture was heated to 100 °C for 1 hour. Upon cooling to room temperature, saturated NH 4Cl solution (100 mL) was added. The reaction mixture was stirred for 30 minutes and was extracted with EtOAc (3x). The combined organic extracts were dried over MgSO 4, filtered, and concentrated. The product was purified via flash column chromatography, eluting with a Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 gradient of 0-70% EtOAc in hexanes, to afford the title compound. The enantiomers were separated via chiral HPLC (Phenomenex Lux Amylose-1, 21.2 x 250 mm, 5 μM, loading: 1mg in 2.8 mL EtOH, eluting with 45% EtOH in hexanes at 20 mL/min). Peak 1 retention time: 8.3 min, Peak 2 retention time: 13.7 min. Peak 1 was the major enantiomer and was used in Step 6 (1.1 g, 33%). Peak 1 is believed to be the (S)-enantiomer (see stereochemical rationale vide supra). LCMS for C 14H 15ClF 2N 3O 2 (M+H)+: monoisotopic m/z = 330.1, found: 330.1. Step 6. 3-Amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylic acid (single enantiomer prepared) A solution of 2-(3-(5-amino-6-chloropyrazin-2-yl)-4-methylphenyl)-3,3-difluoropropane-1,2-diol (Peak 1 from Step 5, believed to be the (S)-enantiomer, 1.1 g, 3.mmol) in ethanol (44 mL) was treated with triethylamine (1.9 mL, 13 mmol) and PdCl 2(dppf)-CH 2Cl 2 adduct (0.27 g, 0.33 mmol). Carbon monoxide was bubbled through the mixture and the reaction was heated at 75 °C under an atmosphere of CO for 2.5 hours. Upon cooling to room temperature, the solvent was removed in vacuo. The product was purified via flash column chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to afford ethyl 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylate (1.0 g). LCMS for C 17H 20F 2N 3O 4 (M+H)+: m/z = 368.1, found: 368.1. To a solution of ethyl 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2- methylphenyl)pyrazine-2-carboxylate (1.0 g, 2.7 mmol) in MeOH (22 mL) was added a solution of lithium hydroxide (0.40 g, 17 mmol) in water (22 mL). The reaction mixture was stirred for 1.5 hours and methanol was removed in vacuo. The aqueous mixture was acidified to pH = 3 by the addition of 1.0 N HCl, saturated with NaCl, and extracted with EtOAc (4x). The combined organic extracts were dried over Na 2SO 4, filtered and concentrated to afford the title compound, which was used without further purification (1.0 g, 88%). LCMS for C 15H 16F 2N 3O 4 (M+H)+: m/z = 340.1, found: 340.1. Step 7. 3-Amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide (single enantiomer prepared) 30 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 To a solution of 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxylic acid (from Step 6, believed to be the (S)-enantiomer, 1.g, 2.9 mmol) in DMF (31 mL) was added HATU (1.5 g, 4.0 mmol) and N,N-diisopropylethylamine (2.2 mL, 12 mmol). To this mixture was added 4-aminobicyclo[2.1.1]hexane-1-carbonitrile, HCl salt (0.59 g, 3.7 mmol, from Example 40, Step 3). The reaction was stirred for 30 minutes and the mixture was diluted with EtOAc. The organic solution was washed with water (2x). The combined aqueous layers were extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified via flash column chromatography, eluting with a gradient of 0-70% EtOAc in hexanes, to afford a yellow oil (1.1 g). This product was subjected to purification via preparative HPLC-MS (pH 10) and lyophilized to afford the title compound (0.68 g, 50%). The product is believed to be the (S)-enantiomer (see stereochemical rationale vide supra). LCMS for C 22H 24F 2N 5O 3 (M+H)+: m/z = 444.2, found: 444.2. H NMR (500 MHz, DMSO-d 6) δ 8.92 (s, 1H), 8.35 (s, 1H), 7.57 (br s, 2H), 7.53 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.0, 1.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.19 (t, J = 55.6 Hz, 1H), 5.80 (s, 1H), 5.08 (s, 1H), 3.77 (d, J = 11.2 Hz, 1H), 3.68 (d, J = 11.0 Hz, 1H), 2.35 – 2.33 (m, 2H), 2.32 (s, 3H), 2.05 – 1.99 (m, 2H), 1.97 – 1.95 (m, 2H), 1.95 – 1.90 (m, 2H). F NMR (470 MHz, DMSO-d 6) δ -129.72 (dd, J = 277.3, 55.1 Hz), -134.28 (dd, J = 277.4, 56.Hz). Example A. THP-1 RPS6 ELISA AssayTo measure the Phosphorylated Ribosomal Protein S6 (RPS6) in cell lysates, THP-cells (Human Acute Monocytic Leukemia) are purchased from ATCC (Manassas, VA) and maintained in RPMI with 10% FBS (Gibco/Life Technologies, Carlsbad, CA). For the assay, THP-1 cells are serum starved overnight in RPMI, then plated in RPMI (2x10 cells/well in 90 μL) into 96-well flat-bottom tissue culture treated plates (Corning, Corning, NY), in the presence or absence of a concentration range of test compounds. Covered plates are incubated for 2 hours at 37 °C, 5% CO 2 then treated with or without 10 nM MCP-1(MYBioSource, San Diego, CA) for 15 minutes at 37 °C, 5% CO 2. Plates are centrifuged at 1600 RPM and supernatants are removed. Cells are lysed in Lysis Buffer (Cell Signaling, Danvers, MA) with Protease Inhibitor (Calbiochem/EMD, Germany), PMSF (Sigma, St Louis MO), HALTS (Thermo Fisher, Rockford, IL) for 30 min on wet ice. Cell lysates are frozen at -80 °C before testing. The lysates are tested in the Human/Mouse/Rat Phospho-RPS6 ELISA (R&D Systems, Inc. Minn, MN). The plate is measured using a microplate reader (SpectraMax M5 – Molecular Devices, LLC Sunnyvale, CA) set to 450 nm with a wavelength correction of 540. 35 Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 IC 50 determination is performed by fitting the curve of inhibitor percent inhibition versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software. Example B. PI3K-γ scintillation proximity assay Materials: [γ-P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPA Scintillation Beads was purchased from Perkin Elmer (Waltham, MA). Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked (PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (Salt Lake City, UT). PI3Kγ (p110γ) Recombinant Human Protein was purchased from Life technology (Grand Island, NY ). ATP, MgCl 2, DTT, EDTA, MOPS and CHAPS were purchased from Sigma Aldrich (St. Louis, MO). The kinase reaction was conducted in polystyrene 384-well Greiner Bio-one white plate from Thermo Fisher Scientific in a final volume of 25 μL. Inhibitors were first diluted serially in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 2%. The PI3Kγ assay was carried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl 2, 5 mM DTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP, the final reaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-P] ATP, 13 nM PI3Kγ. Reactions were incubated for 120 min and terminated by the addition of 40 μL SPA beads suspended in quench buffer: 163 mM potassium phosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads is 1.0 mg/mL. After the plate sealing, plates were shaken overnight at room temperature and centrifuged at 1500 rpm for 10 min, the radioactivity of the product was determined by scintillation counting on Topcount (Perkin–Elmer). IC determination was performed by fitting the curve of percent of the solvent control activity versus the log of the inhibitor concentration using the GraphPad Prism 6.0 software. Example C. PI3Kδ scintillation proximity assayMaterials: [γ-P]ATP (10 mCi/mL) and Wheat Germ Agglutinin (WGA) YSi SPA Scintillation Beads was purchased from Perkin Elmer (Waltham, MA). Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)D (+)-sn-1,2-di-O- octanoylglyceryl, 3-O-phospho linked (PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (Salt Lake City, UT). PI3Kδ (p110δ /p85α) Recombinant Human Protein was purchased from Eurofins (St Charles, MO). ATP, MgCl 2, DTT, EDTA, MOPS and CHAPS were purchased from Sigma Aldrich (St. Louis, MO).
Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 The kinase reaction was conducted in polystyrene 384-well Greiner Bio-one white plate from Thermo Fisher Scientific in a final volume of 25 μL. Inhibitors were first diluted serially in DMSO and added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 2%. The PI3Kδ assay was carried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl 2, 5 mM DTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP, the final reaction mixture consisted of 20 μM PIP2, 2 μM ATP, 0.5 μCi [γ-P] ATP, 3.4 nM PI3Kδ. Reactions were incubated for 120 min and terminated by the addition of 40 μL SPA beads suspended in quench buffer: 163 mM potassium phosphate pH 7.8, 20% glycerol, 25 mM EDTA. The final concentration of SPA beads is 1.0 mg/mL. After the plate sealing, plates were shaken overnight at room temperature and centrifuged at 1500 rpm for 10 min, the radioactivity of the product was determined by scintillation counting on Topcount (PerkinElmer). IC determination was performed by fitting the curve of percent of the solvent control activity versus the log of the inhibitor concentration using the GraphPad Prism 6.0 software. The compounds of the Examples were tested in the assays described in Examples A, B, and C and found to have the IC 50s are shown in Table A. Table A.
Ex. No. PI3Kγ IC 50 (nM) PI3Kδ IC 50 (nM) PI3Kγ_THP1_RPS6_ELISA IC 50 (nM) 1a + + # 1b ++ ++ NA 2 + + # 3 + + # 4 + + # 5 + + # 6 + + # 7 + + # 9 + + # 10 + + # 11 + + # 12 + + # 13 + + # 14 + + # 15 + + ## 16 + + # 17 + + # 18 + + # 19 + ++ ## 20 + ++ NA 21 + + # 22 + ++ # 23 + ++ ## 24 + ++ ## Attorney Docket No.: 20443-0548WO1 (INCY0258-WO1) 1 Ex. No. PI3Kγ IC 50 (nM) PI3Kδ IC 50 (nM) PI3Kγ_THP1_RPS6_ELISA IC 50 (nM) 25 + ++ NA 26 + + # 27 + ++ # 28 + ++ # 29 + + # 30 + + # 31 + + # 32 + + # 33 + + # 34 + + # 35 + + # 36 + + ## 37 + + # 38 + +++ ## 39 + +++ ## 40 + + # 41 + + # 42 + + # 43 + ++ ## 44 + + # 45 + +++ ## 46 + + # 47 + + # 48 + + # + refers to IC 50 of ≤ 100 nM; ++ refers to IC 50 of ≤ 500 nM; +++ refers to an IC 50 of < 20nM; ++++ refers to an IC 50 of ≥ 2000 nM. # refers to IC 50 of ≤ 100 nM; ## refers to IC 50 of ≤ 500 nM; ### refers to IC 50 of < 1000 nM; #### refers to an IC 50 of ≥ 1000 nM. NA refers to data not available. Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety. 10

Claims (59)

1./ 1 Claims 1. A compound of Formula (I): X N NH RR RRHOHO RR R (I) or a pharmaceutically acceptable salt thereof; wherein: X is N or CR; R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2; R is C(O)NRc1Rd1; R, R and R are each independently selected from H, D, halo, CN, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-6 alkyl, HO-C 1-6 alkyl, C 1-6 alkoxy-C 1-alkyl, C 3-6 cycloalkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C(O)NRcRd, wherein the C 1-6 alkyl is optionally substituted by 1, 2, or 3 D; R, R and R are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, C(O)Rb3, C(O)NRc3Rd3, C(O)NRc3(ORa3), and C(O)ORa3, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of R, R, and R are each optionally substituted with 1, 2, or 3 independently selected RB substituents; and wherein the C 1-6 haloalkyl of R, R, or R is optionally substituted by 1, 2, 3, or 4 independently selected Y substituents; each Y is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or independently selected RB substituents; or R and R substituents, together with the ring atoms to which they are attached, form a C 3-cycloalkyl or 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or independently selected RB substituents; 277071/ 1 Rc and Rd are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents; each Ra3, Rb3, Rc3, and Rd3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra3, Rb3, Rc3, and Rd3 are each optionally substituted with 1, 2, or independently selected RB substituents; each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, S(O)Rb4, and S(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of RA is optionally substituted with 1, 2, or 3 independently selected RD substituents; each RB is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered 277071/ 1 heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa2, SRa2, NHORa2, C(O)Rb2, C(O)NRc2Rd2, C(O)NRc2(ORb2), C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, NRc2Rd2, NRc2NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, S(O)Rb2, and S(O) 2Rb2, ; each Ra2, Rb2, Rc2, and Rd2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-; or, any Rc2 and Rd2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-, 5-, 6-, or 7-membered heterocycloalkyl group; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, or independently selected RD substituents; each RD is independently selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa5, SRa5, NHORa5, C(O)Rb5, C(O)NRc5Rd5, C(O)NRc5(ORb5), C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, S(O)Rb5, and S(O) 2Rc5; and each Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is H, D or C 1-6 alkyl.
3. The compound of any one of claims 1 and 2, wherein each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 277071/ 1 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, ORa4, SRa4, NHORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)NRc4(ORb4), C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, S(O)Rb4, and S(O) 2Rb4, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-aryl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of RA are each optionally substituted with 1, 2, or 3 independently selected RD substituents; each Ra4, Rb4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl- of Ra4, Rb4, Rc4, and Rd4 are each optionally substituted with 1, 2, or 3 independently selected RD substituents; and each RD is independently selected from D, OH, NO 2, CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di(C 1-alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-4 alkoxycarbonyl, and C 1-6 alkylcarbonylamino.
4. The compound of any one of claims 1-3, wherein each RA is independently selected from D, halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, ORa4, and NRc4Rd4; wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA are each optionally substituted with 1, 2, or 3 independently selected RD substituents; each Ra4, Rc4, and Rd4 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl, wherein the C 1-6 alkyl of Ra4, Rc4, and Rd4 are each optionally substituted with 1, 2, or 3 independently selected RD substituents; and each RD is independently selected from D, OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.
5. The compound of any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered 277071/ 1 heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents.
6. The compound of any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein: each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, CN, NO 2 and ORa4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA is optionally substituted with 1 or 2 independently selected RD substituents; each Ra4 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted CN, NO 2 or OH; and each RD is OH.
7. The compound of any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein: Rc1 is H; Rd1 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, phenyl-C 1-4 alkyl-, and C 3-7 cycloalkyl-C 1-4 alkyl- of Rc1 and Rd1 are each optionally substituted with 1 or independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituent; and 277071/ 1 each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, -CH 2OH, CN and OH.
8. The compound of any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, wherein: Rc1 is H; Rd1 is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclopbutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrorolidinyl and thianyl of Rd1 are each optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, for a azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; and each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, -CH 2OH, CN and OH.
9. The compound of any claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, D, halo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, CN, OH, and NH 2, wherein C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
10. The compound of any claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is C 1-alkyl, which is optionally substituted with 1, 2, or 3 D.
11. The compound of any claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is methyl or CD 3.
12. The compound of any claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is methyl.
13. The compound of any claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R is CD 3. 277071/ 1
14. The compound of any claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R is H, D, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
15. The compound of any claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R is H.
16. The compound of any claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R is H, D, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
17. The compound of any claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R is H.
18. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2, OH, COOH, and NH 2, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
19. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2, OH, COOH and NH 2, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
20. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is H, D, C 1-6 alkyl or C 1-6 haloalkyl, wherein each halogen is F, wherein the haloalkyl is optionally substituted with 1 or 2 independently selected Y substituents, wherein each Y substituent is independently selected from D, halo, C 1-6 alkyl, and C 1-6 haloalkyl.
21. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is C 1-6 haloalkyl, wherein each halogen is F.
22. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is H, CH 2F, CHF 2 or CF 3.
23. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is CH 2F, CHF 2 or CF 3. 277071/ 1
24. The compound of any claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R is CF 3.
25. The compound of any claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
26. The compound of any claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R is H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
27. The compound of any claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R is methyl or ethyl.
28. The compound of any claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R is H.
29. The compound of any claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
30. The compound of any claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R is H, D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 D.
31. The compound of any claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R is methyl or ethyl.
32. The compound of any claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R is H.
33. The compound of any claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R and R, together with the C atom to which they are attached, form a cyclopropyl or cyclobutyl. 277071/ 1
34. The compound of any claims 1-33, having Formula (II): N N NH RR RRHOHO RR R (II) or a pharmaceutically acceptable salt thereof.
35. The compound of any claims 1-33, having Formula (III): N NH RR RRHOHO RR R R (III) or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; R is C(O)NRc1Rd1; each Rc1 and Rd1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl-, C 3-10 cycloalkyl-C 1-6 alkyl-, (5-10 membered heteroaryl)-C 1-6 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl- of Rc1 and Rd1 are each optionally substituted with 1, 2, or 3 independently selected RA substituents; 277071/ 1 or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, wherein the 4-, 5-, 6-, or 7-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected RA substituents; each RA is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-alkynyl, CN, NO 2 and ORa4, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of RA is optionally substituted with 1 or 2 independently selected RD substituents; each Ra4 is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted CN, NO 2 or OH; each RD is OH; each R, R, and R is independently selected from H, D, halo, CN, OH, C 1-3 alkyl, and C 1-haloalkyl, wherein the C 1-3 alkyl is optionally substituted by 1, 2, or 3 D; and each R, R, and R is independently selected from H, D, C 1-6 alkyl and C 1-6 haloalkyl. 277071/ 1
37. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is N; R is C(O)NRc1Rd1; Rc1 is H; Rd1 is selected from ethyl, propyl, isopropyl, butyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and thianyl, wherein the ethyl, propyl, isopropyl, tert-butyl, cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-phenyl, ethyl-phenyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and thianyl of Rd1 is optionally substituted with 1 or 2 independently selected RA substituents; or, any Rc1 and Rd1, attached to the same N atom, together with the N atom to which they are attached, form an azetidinyl or pyrrolidinyl, wherein the azetidinyl or pyrrolidinyl is optionally substituted with 1 or 2 independently selected RA substituents; each RA is independently selected from oxo, methyl, CH 2F, CHF 2, CF 3, -OCH 3, -CH 2OH, CN, and OH; R is selected from H, methyl, and CD 3; R and R are each H; R is selected from CH 2F, CHF 2 and CF 3; and R and R are each H.
38. The compound of claim 1, selected from: 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide; 3-amino-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxybutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-6-(2-methyl-5-(1,1,1-trifluoro-2,3-dihydroxy-3-methylbutan-2-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-N-((1S,3R)-3-cyanocyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1S,2S)-2-hydroxycyclohexyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 277071/ 1 3-amino-N-((trans)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1S,3R)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((1S,3R)-3-hydroxy-1-methylcyclobutyl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((S)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(2-cyano-2-methylpropyl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-N-((R)-1-hydroxypropan-2-yl)-6-(2-(methyl-d 3)-5-((S)-1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-hydroxybicyclo[2.1.1]hexan-1-yl)-6-(2-(methyl-d 3)-5-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)phenyl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1S,2S)-2-hydroxycyclohexyl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazine-2-carboxamide; (S)-3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d 3)phenyl)pyrazine-2-carboxamide; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-((S)-1-hydroxypropan-2-yl)pyrazine-2-carboxamide; 3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(4-hydroxybicyclo[2.2.1]heptan-1-yl)pyrazine-2-carboxamide; 277071/ 1 (3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazin-2-yl)((R)-2-(hydroxymethyl)pyrrolidin-1-yl)methanone; (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-isopropylpyrazine-2-carboxamide; 3-amino-6-(5-((S)-1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(3-methyltetrahydrofuran-3-yl)pyrazine-2-carboxamide; and 3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)pyrazine-2-carboxamide; or a pharmaceutically acceptable salt thereof.
39. The compound of claim 1, that is (S)-3-amino-N-(4-cyanobicyclo[2.1.1]hexan-1-yl)-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-(methyl-d3)phenyl)pyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof.
40. The compound of claim 1, that is (S)-3-amino-6-(5-(1,1-difluoro-2,3-dihydroxypropan-2-yl)-2-methylphenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof.
41. A pharmaceutical composition comprising a compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
42. A method of inhibiting an activity of PI3Kγ kinase, comprising contacting the kinase with a compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof.
43. The method of claim 42, wherein the compound, or a pharmaceutically acceptable salt thereof, is a selective inhibitor for PI3Kγ over one or more of PI3Kα, PI3Kβ, and PI3Kδ.
44. A compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with abnormal expression or activity of PI3Kγ kinase.
45. The compound of claim 44, wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease. 277071/ 1
46. The compound of claim 44, wherein the disease or disorder is lung cancer, melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, seminoma, teratocarcinoma, astrocytoma, neuroblastoma, glioma, or sarcoma.
47. The compound of claim 46, wherein the sarcoma is Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, or undifferentiated pleomorphic sarcoma.
48. The compound of claim 44, wherein the disease or disorder is acute myeloid leukemia, acute monocytic leukemia, small lymphocytic lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma, large granular lymphocytic leukemia, mature (peripheral) t-cell neoplasm (PTCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma.
49. The compound of claim 48, wherein the mature (peripheral) t-cell neoplasm (PTCL) is T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, mycosis fungoides/Sezary syndrome, anaplastic large cell lymphoma (T-cell type), enteropathy type T-cell lymphoma, adult T-cell leukemia/lymphoma, or angioimmunoblastic T-cell lymphoma.
50. The compound of claim 48, wherein the anaplastic large cell lymphoma (ALCL) is systemic ALCL or primary cutaneous ALCL.
51. The compound of claim 44, wherein the disease or disorder is Burkitt's lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, Mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, xeroderoma pigmentosum, keratoacanthoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, Waldenstrom's macroglobulinemia, prolymphocytic leukemia, acute lymphoblastic leukemia, myelofibrosis, mucosa-associated lymphatic tissue (MALT) lymphoma, mediastinal (thymic) large B-cell 277071/ 1 lymphoma, lymphomatoid granulomatosis, splenic marginal zone lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, plasma cell leukemia, extramedullary plasmacytoma, smoldering myeloma (aka asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), or diffuse large B cell lymphoma.
52. The compound of claim 51, wherein the non-Hodgkin’s lymphoma (NHL) is relapsed NHL, refractory NHL, recurrent follicular NHL, indolent NHL (iNHL), or aggressive NHL (aNHL).
53. The compound of claim 51, wherein the diffuse large B cell lymphoma is activated B-cell like (ABC) diffuse large B cell lymphoma, or germinal center B cell (GCB) diffuse large B cell lymphoma.
54. The compound of claim 51, wherein the Burkitt’s lymphoma is endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma, or Burkitt's-like lymphoma.
55. The compound of claim 44, wherein the disease or disorder is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, asthma, allergy, allergic rhinitis, pancreatitis, psoriasis, anaphylaxis, glomerulonephritis, inflammatory bowel disease, thrombosis, meningitis, encephalitis, diabetic retinopathy, benign prostatic hypertrophy, myasthenia gravis, Sjögren’s syndrome, osteoarthritis, restenosis, or atherosclerosis.
56. The compound of claim 44, wherein the disease or disorder is heart hypertrophy, cardiac myocyte dysfunction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), chronic bronchitis, elevated blood pressure, ischemia, ischemia-reperfusion, vasoconstriction, anemia, bacterial infection, viral infection, graft rejection, kidney disease, anaphylactic shock fibrosis, skeletal muscle atrophy, skeletal muscle hypertrophy, angiogenesis, sepsis, graft-versus-host disease, allogeneic or xenogeneic transplantation, glomerulosclerosis, progressive renal fibrosis, idiopathic thrombocytopenic purpura (ITP), autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, or membranous nephropathy.
57. The compound of claim 56, wherein the idiopathic thrombocytopenic purpura (ITP) is relapsed ITP or refractory ITP.
58. The compound of claim 56, wherein the vasculitis is Behçet's disease, Cogan's syndrome, giant cell arteritis, polymyalgia rheumatica (PMR), Takayasu's arteritis, Buerger's disease (thromboangiitis 277071/ 1 obliterans), central nervous system vasculitis, Kawasaki disease, polyarteritis nodosa, Churg-Strauss syndrome, mixed cryoglobulinemia vasculitis (essential or hepatitis C virus (HCV)-induced), Henoch-Schönlein purpura (HSP), hypersensitivity vasculitis, microscopic polyangiitis, Wegener's granulomatosis, or anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV).
59. The compound of claim 44, wherein the disease or disorder is Alzheimer's disease, central nervous system trauma, or stroke.
IL277071A 2018-03-08 2019-03-07 AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS IL277071B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862640276P 2018-03-08 2018-03-08
US201862702230P 2018-07-23 2018-07-23
US201862745873P 2018-10-15 2018-10-15
PCT/US2019/021186 WO2019226213A2 (en) 2018-03-08 2019-03-07 AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Publications (3)

Publication Number Publication Date
IL277071A IL277071A (en) 2020-10-29
IL277071B1 true IL277071B1 (en) 2024-03-01
IL277071B2 IL277071B2 (en) 2024-07-01

Family

ID=67844335

Family Applications (2)

Application Number Title Priority Date Filing Date
IL277071A IL277071B2 (en) 2018-03-08 2019-03-07 AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS
IL302529A IL302529B1 (en) 2018-03-08 2019-03-07 AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Family Applications After (1)

Application Number Title Priority Date Filing Date
IL302529A IL302529B1 (en) 2018-03-08 2019-03-07 AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS

Country Status (32)

Country Link
US (3) US10669262B2 (en)
EP (2) EP4056560A1 (en)
JP (2) JP7268049B2 (en)
KR (1) KR20200142508A (en)
CN (2) CN112074505B (en)
AU (2) AU2019272342B2 (en)
BR (1) BR112020018094A2 (en)
CA (1) CA3093445A1 (en)
CL (1) CL2020002275A1 (en)
CO (1) CO2020012169A2 (en)
CR (2) CR20200464A (en)
CY (1) CY1125169T1 (en)
DK (1) DK3762368T3 (en)
EC (1) ECSP20061378A (en)
ES (1) ES2910071T3 (en)
HR (1) HRP20220331T1 (en)
HU (1) HUE057970T2 (en)
IL (2) IL277071B2 (en)
LT (1) LT3762368T (en)
MA (1) MA54133B1 (en)
MD (1) MD3762368T2 (en)
MX (2) MX2020009228A (en)
PE (1) PE20210641A1 (en)
PH (1) PH12020551390A1 (en)
PL (1) PL3762368T3 (en)
PT (1) PT3762368T (en)
RS (1) RS63124B1 (en)
SG (1) SG11202008560VA (en)
SI (1) SI3762368T1 (en)
TW (2) TW202413336A (en)
UA (1) UA128288C2 (en)
WO (1) WO2019226213A2 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI3740481T3 (en) 2018-01-19 2024-07-30 Cytokinetics Inc Dihydrobenzofuran and inden analogs as cardiac sarcomere inhibitors
TWI796596B (en) 2018-02-13 2023-03-21 美商基利科學股份有限公司 Pd-1/pd-l1 inhibitors
IL277071B2 (en) 2018-03-08 2024-07-01 Incyte Corp AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS
WO2020005887A1 (en) 2018-06-26 2020-01-02 Cytokinetics, Inc. Cardiac sarcomere inhibitors
WO2020010003A1 (en) 2018-07-02 2020-01-09 Incyte Corporation AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS
CN112341437A (en) * 2020-12-21 2021-02-09 李寒 Substituted pyrazine derivative and application thereof
IL305628A (en) 2021-03-04 2023-11-01 Cytokinetics Inc Cardiac sarcomere inhibitors

Family Cites Families (810)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2190837B1 (en) 1972-06-29 1974-12-27 Rhone Progil
US4705853A (en) 1982-09-30 1987-11-10 A. H. Robins Company, Inc. Fused aromatic oxazepinones, thiazepinones, diazepinones and sulfur analogs thereof
US5025096A (en) 1985-08-22 1991-06-18 Mine Safety Appliances Company Preparation of indole and indole derivatives
US4861884A (en) 1985-10-15 1989-08-29 The Dow Chemical Company Compositions prepared from amino substituted pyrazines and carboxylic acids, carboxylic acid anhydrides, carboxylic acid esters or carboxylic acid halides
GB8718445D0 (en) 1987-08-04 1987-09-09 Wyeth John & Brother Ltd Pyridyl-ethers
JP2691986B2 (en) 1987-08-28 1997-12-17 チッソ株式会社 Process for producing optically active compound having pyridine skeleton
NL9001162A (en) 1990-05-18 1991-12-16 Stamicarbon PROCESS FOR PREPARING 2-N-ACYLAMINOPYRIDINES AND 2-AMINOPYRIDINES FROM 5-OXOALCANE NITRILOXIMMS AND THESE 5-OXOALCANE NITRILOXIMMS, 2-N-ACYLAMINOPYRIDINES AND 2-AMINOPYRIDINES
US5155117A (en) 1991-04-12 1992-10-13 G. D. Searle & Co. 1-arylheteroarylalkyl substituted-1h-1,2,4-triazole compounds for treatment of circulatory disorders
JPH0558997A (en) 1991-09-04 1993-03-09 Mitsubishi Kasei Corp Thiocarbamoylacetonitrile derivative
DE69311145T2 (en) 1992-01-23 1998-02-05 Inst Francais Du Petrol Catalyst for the alkylation of olefins
US5315043A (en) 1992-02-05 1994-05-24 E. I. Du Pont De Nemours And Company Aromatic nucleophilic fluorination
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
US5252737A (en) 1992-05-22 1993-10-12 Monsanto Company Process for preparing N-aliphatic substituted p-phenylenediamines
JPH061776A (en) 1992-06-18 1994-01-11 Nippon Soda Co Ltd Production of substituted pyrazinecarbonitrile
US5232945A (en) 1992-07-20 1993-08-03 Pfizer Inc. 3-aryl-2-hydroxypropionic acid derivatives and analogs as antihypertensives
JP4327911B2 (en) 1993-03-03 2009-09-09 日本曹達株式会社 Method for producing imide compound
JPH06256327A (en) 1993-03-03 1994-09-13 Nippon Soda Co Ltd Production of 4-substituted azetidinone derivative
WO1994022853A1 (en) 1993-03-26 1994-10-13 Shell Internationale Research Maatschappij B.V. Herbicidal 1-heteroaryl pyrazolidin-3,5-diones
US5545535A (en) 1993-04-13 1996-08-13 Molecular Probes, Inc. Fluorescent assay for bacterial gram reaction
US5534416A (en) 1993-04-13 1996-07-09 Molecular Probes, Inc. Fluorescent viability assay using cyclic-substituted unsymmetrical cyanine dyes
US5436134A (en) 1993-04-13 1995-07-25 Molecular Probes, Inc. Cyclic-substituted unsymmetrical cyanine dyes
US5451702A (en) 1993-04-26 1995-09-19 Monsanto Company Process for preparing substituted aromatic amines
TW266206B (en) 1993-04-28 1995-12-21 Takeda Pharm Industry Co Ltd
JPH0782249A (en) 1993-06-30 1995-03-28 Nippon Soda Co Ltd Production of 4-substituted azetidinone derivative
US5602156A (en) 1993-09-17 1997-02-11 The United States Of America As Represented By The Department Of Health And Human Services Method for inhibiting metalloproteinase expression
US5744492A (en) 1993-09-17 1998-04-28 United States Of America Method for inhibiting angiogenesis
US5430123A (en) 1994-02-04 1995-07-04 Hoechst Celanese Corporation Polymer compositions containing substituted pyrazines
US5393860A (en) 1994-02-04 1995-02-28 Hoechst Celanese Corporation Polymer compositions containing substituted pyrazines
US5459266A (en) 1994-02-04 1995-10-17 Hoechst Celanese Corporation Substituted pyrazines
ATE243196T1 (en) 1994-03-09 2003-07-15 Novo Nordisk As PIPERIDINE AND PYRROLIDINE
US5863903A (en) 1994-03-09 1999-01-26 Novo Nordisk A/S Use of hydroxy alkyl piperidine and pyrrolidine compounds to treat diabetes
DE19509353A1 (en) 1994-03-31 1995-10-05 Basf Ag New 4-aminopiperidine cpds., useful in e.g. plant protection
SE9401353D0 (en) 1994-04-21 1994-04-21 Pharmacia Ab Novel antitumour compounds with antimitotic activity
DE4417746A1 (en) 1994-05-20 1995-11-23 Bayer Ag New dyes for mass coloring plastics
KR0151819B1 (en) 1994-06-11 1998-10-15 강박광 Novel pyridylimidazole derivatives substituted with pyridyl n-oxide and process for the preparation thereof
GB9412522D0 (en) 1994-06-22 1994-08-10 Ici Plc Optical recording media
DE4427529A1 (en) 1994-08-04 1996-02-08 Bayer Ag Process for the preparation of 1,2,4-triazine-3,5-diones
FR2725718B1 (en) 1994-10-14 1997-01-24 Virbac Lab BIS-2-AMINOPYRIDINES, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS
US5883106A (en) 1994-10-18 1999-03-16 Pfizer Inc. 5-lipoxygenase inhibitors
SK281577B6 (en) 1994-10-18 2001-05-10 Pfizer Inc. Heterocyclic compositions and pharmaceutical agent based on them
JPH08175994A (en) 1994-10-27 1996-07-09 Takeda Chem Ind Ltd Lipometabolism-improving agent
RO118715B1 (en) 1994-10-27 2003-09-30 Janssen Pharmaceutica Nv Apolipoprotein-b synthesis inhibitors
US5705512A (en) 1994-11-10 1998-01-06 Sibia Neurosciences, Inc. Modulators of acetylcholine receptors
US5677459A (en) 1994-11-10 1997-10-14 Sibia Neurosciences, Inc. Methods for the preparation of modulators of acetylcholine receptors
US5703100A (en) 1994-11-10 1997-12-30 Sibia Neurosciences, Inc. Modulators of acetylcholine receptors
US5723477A (en) 1994-11-10 1998-03-03 Sibia Neurosciences, Inc. Modulators of acetylcholine receptors
US6057346A (en) 1994-12-12 2000-05-02 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of retroviral LTR promoters by calcium response modifiers
US5521056A (en) 1995-01-10 1996-05-28 Eastman Kodak Company Photographic peracid bleaching composition and processing method using ternary iron carboxylate complexes as catalysts in peracid bleaching solutions
WO1996021651A1 (en) 1995-01-12 1996-07-18 Otsuka Kagaku Kabushiki Kaisha 4,5-dihydropyrazole-5-thione derivatives and acaricide containing the same
US5656449A (en) 1995-03-06 1997-08-12 Molecular Probes, Inc. Neutral unsymmetrical cyanine dyes
JPH08337583A (en) 1995-04-13 1996-12-24 Takeda Chem Ind Ltd Heterocyclic compound and its production
GB9520355D0 (en) 1995-10-05 1995-12-06 Zeneca Ltd Chemical process
ES2167563T3 (en) 1995-05-23 2002-05-16 Janssen Pharmaceutica Nv DERIVATIVES OF (2-MORFOLINILMETIL) BENZAMIDA.
DE69615844T2 (en) 1995-06-28 2002-05-16 Syngenta Ltd., Haselmere METHOD FOR PRODUCING 2- (6-SUBSTITUTED PYRID-2-YLOXY METHYL) PHENYL ACETATE
AU7095496A (en) 1995-09-26 1997-04-17 Nippon Soda Co., Ltd. Pyrazole compounds, process for preparing the same, and agrohorticultural bactericide
US5756508A (en) 1995-10-31 1998-05-26 Merck & Co., Inc. Muscarine antagonists
WO1997016187A1 (en) 1995-10-31 1997-05-09 Merck & Co., Inc. Muscarine antagonists
AU7528696A (en) 1995-10-31 1997-05-22 Merck & Co., Inc. Muscarine antagonists
GB9525296D0 (en) 1995-12-11 1996-02-07 Merck Sharp & Dohme Therapeutic agents
KR100443893B1 (en) 1996-01-15 2004-10-15 얀센 파마슈티카 엔.브이. Angiogenesis inhibitor pyridazine amine
GB9605331D0 (en) 1996-03-13 1996-05-15 Glaxo Group Ltd Chemical compounds
US5880137A (en) 1996-04-19 1999-03-09 American Home Products Corporation 2-phenyl-1- 4-(amino-1-yl-alk-1-ynyl)-benzyl!-1H-indol-5-ols as estrogenic agents
WO1997043267A1 (en) 1996-05-11 1997-11-20 Kings College London Pyrazines
DE19620508A1 (en) 1996-05-22 1997-11-27 Hoechst Ag Sulfur-containing heterocyclic bradykinin antagonists, process for their preparation and their use
US5672592A (en) 1996-06-17 1997-09-30 Guilford Pharmaceuticals Inc. Certain phosphonomethyl-pentanedioic acid derivatives thereof
FR2751969B1 (en) 1996-08-01 1998-12-04 Centre Nat Rech Scient CFTR CHANNEL ACTIVATING COMPOUNDS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP4278008B2 (en) 1996-08-23 2009-06-10 興和株式会社 Diamide compound and pharmaceutical containing the same
TW382127B (en) 1996-08-30 2000-02-11 Sony Corp Magnetic recording medium and cleaning tape
DE69707907T2 (en) 1996-09-26 2002-05-16 Syngenta Participations Ag, Basel HERBICIDAL COMPOSITION
WO1998014436A1 (en) 1996-10-02 1998-04-09 Dupont Pharmaceuticals Company 4,4-disubstituted-1,4-dihydro-2h-3,1-benzoxazin-2-ones useful as hiv reverse transcriptase inhibitors and intermediates and processes for making the same
US5869487A (en) 1996-10-24 1999-02-09 Merck & Co., Inc. Pyrido 3,4-B!pyrazines for use as thrombin inhibitors
ES2191830T3 (en) 1996-10-24 2003-09-16 Merck & Co Inc THROMBIN INHIBITORS.
US6274598B1 (en) 1996-10-28 2001-08-14 The United States Of America As Represented By The Secretary Of The Army Methods for treating antibiotic-resistant infections
WO1998018326A1 (en) 1996-10-28 1998-05-07 Department Of The Army, U.S. Government Compounds, compositions and methods for treating antibiotic-resistant infections
US20020115678A1 (en) 1996-10-28 2002-08-22 Ellis William Y. Compounds, compositions and methods for treating antibiotic-resistant infections
US6147080A (en) 1996-12-18 2000-11-14 Vertex Pharmaceuticals Incorporated Inhibitors of p38
JPH10188264A (en) 1996-12-24 1998-07-21 Sony Corp Magnetic recording medium and its production
AU5617398A (en) 1996-12-30 1998-07-31 Beacon Laboratories L.L.C. Tricarboxylic acid-containing oxyalkyl esters and uses thereof
JP2001512460A (en) 1997-02-18 2001-08-21 イー・アイ・デユポン・ドウ・ヌムール・アンド・カンパニー Herbicidal tetrazolinones
JPH10324687A (en) 1997-02-19 1998-12-08 Nippon Soda Co Ltd Pyrrole compound, production and agricultural and horticultural microbicide
US5811442A (en) 1997-02-21 1998-09-22 Bencherif; Merouane Pharmaceutical compositions for the treatment of conditions associated with decreased blood flow
DE19718742A1 (en) 1997-05-02 1998-11-05 Hoechst Ag Aromatic aldehyde production from carboxylic acids
FR2763334A1 (en) 1997-05-13 1998-11-20 Lipha Piperazino alkyl anthranilic acid amide
FR2763588B1 (en) 1997-05-23 1999-07-09 Cird Galderma TRIAROMATIC COMPOUNDS, COMPOSITIONS CONTAINING THEM, AND USES
GB9711753D0 (en) 1997-06-06 1997-08-06 Merck Sharp & Dohme Therapeutic agents
CA2293418A1 (en) 1997-06-19 1998-12-23 Michael Z. Hoemann Quinoline-indole antimicrobial agents, uses and compositions related thereto
US6207679B1 (en) 1997-06-19 2001-03-27 Sepracor, Inc. Antimicrobial agents uses and compositions related thereto
WO1999001453A1 (en) 1997-07-02 1999-01-14 F. Hoffmann-La Roche Ag A process for the manufacture of optically active chromanylpyridine derivatives
DE19728996A1 (en) 1997-07-07 1999-01-14 Basf Ag Triazole compounds and their use
JP2001517623A (en) 1997-09-23 2001-10-09 メルク エンド カムパニー インコーポレーテッド Thrombin inhibitors
CA2309347A1 (en) 1997-12-01 1999-06-10 Merck & Co., Inc. Thrombin inhibitors
JP2001526222A (en) 1997-12-22 2001-12-18 バイエル コーポレイション Inhibition of p38 kinase activity using aryl and heteroaryl substituted heterocyclic ureas
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
TR200100918T2 (en) 1997-12-22 2001-06-21 Bayer Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted ureas
US6632823B1 (en) 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
WO1999033810A1 (en) 1997-12-24 1999-07-08 Kumiai Chemical Industry Co., Ltd. Pyridyloxy(thio)alkanoic acid amide derivatives and agricultural/horticultural bactericides
DK0930302T3 (en) 1998-01-16 2003-07-21 Hoffmann La Roche Benzosulfone derivatives
NZ506101A (en) 1998-01-28 2003-06-30 Shionogi & Co Tricyclic immunosupressant, anti-allergic and IgE production suppressant compounds
US7517884B2 (en) 1998-03-30 2009-04-14 Kalypsys Inc. Sulfonyl-substituted bicyclic compounds as modulators of PPAR
JPH11292883A (en) 1998-04-07 1999-10-26 Yoshitomi Fine Chemical Kk Preparation of triphenylboron amine adduct compound
CA2328970A1 (en) 1998-04-27 1999-11-04 Valentin Florent Victor De Conde Pellets having a core coated with a lipid lowering agent and a polymer
BR9910179A (en) 1998-05-02 2001-01-09 Astrazeneca Ab Compound, pharmaceutical composition, use of a compound, and process for treating a disease or condition mediated by factor xa in a warm-blooded animal
EP1085879A2 (en) 1998-06-08 2001-03-28 Advanced Medicine, Inc. Multibinding agents that modulate the 5-ht transporter
US6197798B1 (en) 1998-07-21 2001-03-06 Novartis Ag Amino-benzocycloalkane derivatives
CO5090829A1 (en) 1998-07-21 2001-10-30 Novartis Ag ORGANIC COMPOUNDS OF FORMULA I, USED AS INHIBITED RES OF THE PROTEIN OF TRANSFER OF MICROSOUS TRIGLICERIDE AND OF THE APOLIPOPROTEIN B SECRETION.
YU10101A (en) 1998-08-10 2003-10-31 Partnership Of Michael E. Garst George Sachs And Jai Moo Shin Prodrugs of proton pump inhibitors
BR9912938B1 (en) 1998-08-11 2011-06-28 isoquinoline derivatives, composition comprising them, process for preparation and use thereof.
JP2000073094A (en) 1998-08-28 2000-03-07 Lion Corp Mold removing composition
JP2000076643A (en) 1998-08-31 2000-03-14 Sony Corp Magnetic disk device
JP2000076642A (en) 1998-08-31 2000-03-14 Sony Corp Magnetic recording and reproducing device
JP2000076640A (en) 1998-08-31 2000-03-14 Sony Corp Magnetic recording reproducing device
AR023656A1 (en) 1998-09-15 2002-09-04 Syngenta Participations Ag HERBICIDE PYRIDINCETONES, PROCESS FOR PREPARATION, HERBICIDE AGENTS THAT UNDERSTAND THESE COMPOUNDS AND USE OF THESE AGENTS TO COMBAT THE UNWANTED GROWTH OF PLANTS
US6316267B1 (en) 1998-10-27 2001-11-13 Molecular Probes, Inc. Luminescent protein stains an their method of use
US6133031A (en) 1999-08-19 2000-10-17 Isis Pharmaceuticals Inc. Antisense inhibition of focal adhesion kinase expression
BR9915899A (en) 1998-12-04 2001-08-21 American Home Prod Compound, pharmaceutical composition and method for treating or inhibiting disorders associated with smooth muscle contraction.
AU769890B2 (en) 1998-12-04 2004-02-05 Fujisawa Pharmaceutical Co., Ltd. Sulfonamide compounds and uses thereof as medicines
AR023071A1 (en) 1998-12-23 2002-09-04 Syngenta Participations Ag PIRIDINCETONE COMPOUNDS, INTERMEDIATE COMPOUNDS, HERBICITY AND INHIBITOR COMPOSITION OF PLANTAGE GROWTH, METHOD FOR CONTROLLING INDESATED VEGETATION, METHOD FOR INHIBITING GROWTH OF PLANTS, AND USE OF COMPOSITION TO GROW GROWTH.
US20020103141A1 (en) 1998-12-23 2002-08-01 Mckearn John P. Antiangiogenic combination therapy for the treatment of cancer
GB9901253D0 (en) 1999-01-20 1999-03-10 Isis Innovation Bis-terpyridine-platinum(II) complexes
GB9905075D0 (en) 1999-03-06 1999-04-28 Zeneca Ltd Chemical compounds
DE19932571A1 (en) 1999-07-13 2001-01-18 Clariant Gmbh Process for the preparation of biarylene using palladophosphacyclobutane catalysis
EP1206449A1 (en) 1999-07-26 2002-05-22 Bristol-Myers Squibb Company Lactam inhibitors of hepatitis c virus ns3 protease
US7122627B2 (en) 1999-07-26 2006-10-17 Bristol-Myers Squibb Company Lactam inhibitors of Hepatitis C virus NS3 protease
WO2001016122A1 (en) 1999-08-31 2001-03-08 Maxia Pharmaceuticals, Inc. Benzylidene-thiazolidinediones and analogues and their use in the treatment of diabetes
JP2001072660A (en) 1999-09-08 2001-03-21 Welfide Corp TNF-alpha PRODUCTION INHIBITOR AND/OR IL-10 PRODUCTION PROMOTER
JP4523093B2 (en) 1999-09-20 2010-08-11 広栄化学工業株式会社 Process for producing 2-amino-bromopyrazines
WO2001032658A1 (en) 1999-11-02 2001-05-10 Ajinomoto Co., Inc. Polyazanaphthalene compound and medicinal use thereof
JP2003514816A (en) 1999-11-18 2003-04-22 ノバルティス アクチエンゲゼルシャフト Insecticidal aminoheterocyclamide compounds
AU779230C (en) 1999-12-03 2006-05-25 Emory University Curcumin analogues for treating cancer
GB0004890D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
JP4388189B2 (en) 2000-03-08 2009-12-24 独立行政法人科学技術振興機構 Pyridine derivative and method for producing the same
US6768008B2 (en) 2000-04-24 2004-07-27 Aryx Therapeutics Materials and methods for the treatment of diabetes, hyperlipidemia, hypercholesterolemia, and atherosclerosis
WO2001081328A2 (en) 2000-04-24 2001-11-01 Aryx Therapeutics Thiazolidinedione analogues and their use for the treatment of diabetes
WO2001087853A1 (en) 2000-05-17 2001-11-22 Universite Catholique De Louvain Aryl-substituted n,n-heterocyclic compounds, method for their preparation and their use in therapeutics and diagnostics
WO2003024441A1 (en) 2001-09-14 2003-03-27 Shionogi & Co., Ltd. Novel use of tricyclic compound
KR20030017511A (en) 2000-06-28 2003-03-03 에스에스 세야쿠 가부시키 가이샤 Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts
ES2225624T3 (en) 2000-06-28 2005-03-16 Smithkline Beecham Plc GRINDING PROCEDURE BY WET.
MXPA03000504A (en) 2000-07-19 2003-06-24 Hoffmann La Roche Pyrimidine derivatives.
US6541639B2 (en) 2000-07-26 2003-04-01 Bristol-Myers Squibb Pharma Company Efficient ligand-mediated Ullmann coupling of anilines and azoles
AU2001282990A1 (en) 2000-07-27 2002-02-13 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
JO2654B1 (en) 2000-09-04 2012-06-17 شركة جانسين فارماسوتيكا ان. في Polyarylcarboxamides useful as lipid lowering agents
WO2002024689A1 (en) 2000-09-21 2002-03-28 Aryx Therapeutics Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis
US6706829B2 (en) 2000-11-07 2004-03-16 Symyx Technologies, Inc. Methods of polymerizing ethylene and styrene copolymers with substituted pyridyl amine catalysts and catalysts therefor
WO2002042272A2 (en) 2000-11-20 2002-05-30 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridines useful for selective inhibition of the coagulation cascade
FR2816942B1 (en) 2000-11-23 2003-05-09 Sanofi Synthelabo BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
DE10060807A1 (en) 2000-12-07 2002-06-20 Aventis Pharma Gmbh Ortho, ortho-substituted nitrogen-containing bisaryl compounds, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them
US6610723B2 (en) 2001-01-29 2003-08-26 Hoffmann-La Roche Inc. Imidazole derivatives
KR100844062B1 (en) 2001-02-21 2008-07-07 미쓰이 가가쿠 가부시키가이샤 Catalyst for olefin polymerizaion and method for producing olefin polymers using the catalyst
WO2002070514A1 (en) 2001-03-02 2002-09-12 F. Hoffmann-La Roche Ag Alkoxycarbonylamino heteroaryl carboxylic acid derivatives as ip antagonists
FR2821718B1 (en) 2001-03-08 2003-06-13 Aventis Cropscience Sa NOVEL FUNGICIDAL COMPOSITIONS BASED ON PYRIDYLMETHYLBENZAMIDE AND IMIDAZOLINE OR OXAZOLIDINE DERIVATIVES
AU2002254171A2 (en) 2001-03-08 2002-09-24 Incyte San Diego, Inc. RXR activating molecules
US7012098B2 (en) 2001-03-23 2006-03-14 Pharmacia Corporation Inhibitors of inducible nitric oxide synthase for chemoprevention and treatment of cancers
NZ527012A (en) 2001-03-28 2005-03-24 Pfizer N-phenpropylcyclopentyl-substituted glutaramide derivatives as NEP inhibitors for FSAD
US6858600B2 (en) 2001-05-08 2005-02-22 Yale University Proteomimetic compounds and methods
JP2002338537A (en) 2001-05-16 2002-11-27 Mitsubishi Pharma Corp Amide compound and its medicinal use
JP2002338837A (en) 2001-05-16 2002-11-27 Fuji Photo Film Co Ltd Novel compound, coloring matter, ink composition, ink for ink jet, ink jet recording method and thermal transfer coloring matter
WO2002100196A1 (en) 2001-06-08 2002-12-19 Japan Tobacco Inc. Fluid body coater
JP4180254B2 (en) 2001-06-29 2008-11-12 独立行政法人科学技術振興機構 Method for producing nitrogen-containing 6-membered ring
SE0102438D0 (en) 2001-07-05 2001-07-05 Astrazeneca Ab New compounds
JP4340404B2 (en) 2001-07-23 2009-10-07 独立行政法人科学技術振興機構 Method for producing unsaturated 6-membered ring
MXPA04002243A (en) 2001-09-19 2004-06-29 Aventis Pharma Sa Chemical compounds.
FR2830194B1 (en) 2001-09-28 2003-12-19 Oreal COMPOSITION CONTAINING PYRAZINE DERIVATIVE AND USE FOR DIRECT DYEING OR OXIDATION AND / OR OPTICAL THINNING OF KERATIN FIBERS
FR2831022B1 (en) 2001-10-23 2004-01-23 Aventis Cropscience Sa FUNGICIDAL COMPOSITION BASED ON AT LEAST ONE PYRIDYLMETHYLBENZAMIDE DERIVATIVE AND AT LEAST ONE DITHIOCARBAMATE DERIVATIVE
DE60213842T2 (en) 2001-10-30 2007-09-06 Novartis Ag STAUROSPORINE DERIVATIVES AS INHIBITORS OF THE FLT3 RECEPTOR TYROSINE KINASE EFFECT
US7166368B2 (en) 2001-11-07 2007-01-23 E. I. Du Pont De Nemours And Company Electroluminescent platinum compounds and devices made with such compounds
US7361671B2 (en) 2001-11-15 2008-04-22 The Institute For Pharmaceutical Discovery, Inc. Substituted heteroarylalkanoic acids
JP4416998B2 (en) 2001-11-19 2010-02-17 日本エンバイロケミカルズ株式会社 Microbial control agent
DE10238113A1 (en) 2001-12-11 2003-06-18 Bayer Ag New 2-substituted methylthio-dicyanopyridine derivatives, useful for treating or preventing e.g. cardiovascular disease and inflammation, are adenosine A1 receptor agonists
US7091357B2 (en) 2001-12-26 2006-08-15 University Of Kentucky Research Foundation Chain-modified pyridino-N substituted nicotine compounds for use in the treatment of CNS pathologies
JP2005162612A (en) 2002-01-09 2005-06-23 Ajinomoto Co Inc Acylsulfonamide derivative
EP1465613A2 (en) 2002-01-10 2004-10-13 Boehringer Ingelheim Pharma GmbH &amp; Co. KG Combination of mtp inhibitors or apob secretion inhibitors with fibrates for use as drugs
EP1467733A1 (en) 2002-01-11 2004-10-20 Eli Lilly And Company 2-oxo-benzimidazolyl substituted ethanolamine derivatives and their use as beta3 agonists
EP1470108B1 (en) 2002-01-18 2016-08-24 Vittal Mallya Scientific Research Foundation 1,4-dihydropyridine and pyridine compounds as calcium channel blockers
CA2474322A1 (en) 2002-01-25 2003-07-31 Kylix Pharmaceuticals B.V. 4(hetero-) aryl substituted (thia-/oxa-/pyra) zoles for inhibition of tie-2
DE60334972D1 (en) 2002-02-22 2010-12-30 Pharmacia & Upjohn Co Llc PYRIDYLSULPHON DERIVATIVES AS 5-HT6 RECEPTOR LIGANDS
AU2003213642A1 (en) 2002-02-28 2003-09-16 Rensselaer Polytechnic Institute High-affinity, low-molecular-mass displacers for ion-exchange chromatography
US20050069551A1 (en) 2002-03-08 2005-03-31 Emory University Cytotoxic compound-protein conjugates as suppressors of tumor growth and angiogenesis
US20090011991A1 (en) 2002-03-08 2009-01-08 Emory University Novel Curcuminoid-Factor VIIA Constructs as Suppressors of Tumor Growth and Angiogenesis
US20040127719A1 (en) 2002-03-08 2004-07-01 Kexin Yang Alpha-isocyanocarboxylate solid support templates, method of preparation and for using the same
CN1374306A (en) 2002-03-27 2002-10-16 江苏省农药研究所 Prepn of improved pesticide intermediate
JP2005320249A (en) 2002-05-01 2005-11-17 Banyu Pharmaceut Co Ltd Method for producing 2-aminopyrazine derivative
US20060089400A1 (en) 2002-05-03 2006-04-27 The Vernalis Group Of Companies Novel spiro ketone and carboxylic acid derivatives as specific inhibitors for (po3h2) ser/(po3h2)thr-pro-specific peptidyl-prolylcis/trans-isomerases
US6806265B2 (en) 2002-05-16 2004-10-19 Boehringer Ingelheim International Gmbh Non-nucleoside reverse transcriptase inhibitors
TW200406374A (en) 2002-05-29 2004-05-01 Novartis Ag Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases
AU2003218176A1 (en) 2002-06-11 2003-12-22 Bristol-Myers Squibb Company Asymetric synthesis of amino-pyrrolidinones
GB0215676D0 (en) 2002-07-05 2002-08-14 Novartis Ag Organic compounds
US20040127569A1 (en) 2002-08-02 2004-07-01 Manning Pamela T. Methods for treatment and prevention of gastrointestinal conditions
JP4178008B2 (en) 2002-08-02 2008-11-12 日本エンバイロケミカルズ株式会社 Algae control agent and algae control method
JP2003292408A (en) 2002-08-13 2003-10-15 Takeda Chem Ind Ltd Microorganism controller
SE0202429D0 (en) 2002-08-14 2002-08-14 Astrazeneca Ab Novel Compounds
US20040087590A1 (en) 2002-08-23 2004-05-06 University Of Connecticut Novel biphenyl and biphenyl-like cannabinoids
CA2496577A1 (en) 2002-08-28 2004-03-11 Intermune, Inc. Combination therapy for treatment of fibrotic disorders
JP4513569B2 (en) 2002-08-29 2010-07-28 日本ゼオン株式会社 Transition metal compound, catalyst for conjugated diene polymerization, method for producing conjugated diene polymer, polyisoprene and cyclized product thereof, and method for producing them
JP2004123617A (en) 2002-10-03 2004-04-22 Japan Enviro Chemicals Ltd Microbe-controlling agent
JP4566540B2 (en) 2002-10-03 2010-10-20 日本エンバイロケミカルズ株式会社 Industrial disinfectant, paint, ink, resin emulsion, metalworking fluid, fountain solution
PL376405A1 (en) 2002-10-07 2005-12-27 Artesian Therapeutics, Inc. Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity
US20070066619A1 (en) 2002-10-07 2007-03-22 Artesian Therapeutics, Inc. Compounds having simultaneous ability to block L-type calcium channels and to inhibit phosphodiesterase type 3 activity
JP3587839B2 (en) 2002-10-23 2004-11-10 日本エンバイロケミカルズ株式会社 Method for stabilizing bisquaternary ammonium salt compounds
US20040082641A1 (en) 2002-10-28 2004-04-29 Rytved Klaus Asger Use of glycogen phosphorylase inhibitors for treatment of cardiovascular diseases
FR2846657B1 (en) 2002-11-05 2004-12-24 Servier Lab NOVEL PYRIDOPYRIMIDINONE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
ITMI20022389A1 (en) 2002-11-12 2004-05-13 Nicox Sa DRUGS FOR SEXUAL DYSFUNCTIONS.
CL2003002353A1 (en) 2002-11-15 2005-02-04 Vertex Pharma COMPOUNDS DERIVED FROM DIAMINOTRIAZOLS, INHIBITORS D ELA PROTEINA QUINASA; PHARMACEUTICAL COMPOSITION; PREPARATION PROCEDURE; AND ITS USE OF THE COMPOUND IN THE TREATMENT OF DISEASES OF ALLERGIC DISORDERS, PROLIFERATION, AUTOIMMUNES, CONDIC
AU2003294442A1 (en) 2002-11-22 2004-06-18 Bristol-Myers Squibb Company 3-heterocyclic benzylamide derivatives as potassium channel openers
DE10254596A1 (en) 2002-11-22 2004-06-03 Merck Patent Gmbh indole derivatives
WO2004052890A1 (en) 2002-12-06 2004-06-24 Affinium Pharmaceuticals, Inc. Heterocyclic compounds, methods of making them and their use in therapy
US20040142978A1 (en) 2002-12-12 2004-07-22 Pharmacia Corporation Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase-2
BR0317183A (en) 2002-12-12 2005-11-01 Pharmacia Corp Method of Using Aminocyanopyridine Compounds as Inhibitors of Mitogen-Activated Protein Kinase-Activated Protein Kinase-2
US20040127519A1 (en) 2002-12-12 2004-07-01 Pharmacia Corporation Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors
JP4473503B2 (en) 2002-12-16 2010-06-02 日本エンバイロケミカルズ株式会社 Microbial control agent
SE0203752D0 (en) 2002-12-17 2002-12-17 Astrazeneca Ab New compounds
UA80767C2 (en) 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
ES2215474B1 (en) 2002-12-24 2005-12-16 J. URIACH &amp; CIA S.A. NEW DERIVATIVES OF PHOSPHORAMIDE.
JP3502629B1 (en) 2002-12-26 2004-03-02 日本エンバイロケミカルズ株式会社 Microbial control agent and stabilization method
GB0300783D0 (en) 2003-01-14 2003-02-12 Btg Int Ltd Treatment of neurodegenerative conditions
GB0301350D0 (en) 2003-01-21 2003-02-19 Merck Sharp & Dohme Therapeutic agents
TW200418791A (en) 2003-01-23 2004-10-01 Bristol Myers Squibb Co Pharmaceutical compositions for inhibiting proteasome
JP2006516626A (en) 2003-01-28 2006-07-06 スミスクライン ビーチャム コーポレーション Chemical compound
PE20040945A1 (en) 2003-02-05 2004-12-14 Warner Lambert Co PREPARATION OF SUBSTITUTED QUINAZOLINES
US20060160864A1 (en) 2003-02-07 2006-07-20 Mitsuru Shiraishi Acrylamide derivative, process for producing the same, and use
JP2006517211A (en) 2003-02-10 2006-07-20 バイエル・ヘルスケア・アクチェンゲゼルシャフト Bis (hetero) arylcarboxamide derivatives for use as PGI2 antagonists
GB0305929D0 (en) 2003-03-14 2003-04-23 Novartis Ag Organic compounds
DE10315573A1 (en) 2003-04-05 2004-10-14 Merck Patent Gmbh Substituted pyrazoles
US7129264B2 (en) 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
CA2464604A1 (en) 2003-04-17 2004-10-17 Queen's University At Kingston Organic luminescent compounds and methods of making and using same
DE10318609A1 (en) 2003-04-24 2004-11-11 Elbion Ag 5-hydroxyindoles with N-oxide groups and their use as therapeutic agents
DE10318610A1 (en) 2003-04-24 2004-11-11 Elbion Ag 7-azaindoles and their use as therapeutic agents
DE10318611A1 (en) 2003-04-24 2004-11-11 Elbion Ag 4-, 6- or 7-hydroxyindoles with N-oxide groups and their use as therapeutic agents
EP1837330B1 (en) 2003-05-12 2012-10-24 Pfizer Products Inc. Benzamide inhibitors of the P2X7 receptor
GB0311081D0 (en) 2003-05-14 2003-06-18 Btg Internat Limted Treatment of neurodegenerative conditions
WO2004104052A1 (en) 2003-05-21 2004-12-02 Basell Polyolefine Gmbh Transition-metal complexes with tridentate, nitrogen-containing ligands
AU2003902860A0 (en) 2003-06-06 2003-06-26 Daicel Chemical Industries, Ltd Benzimidazole compounds
CA2526506A1 (en) 2003-06-09 2004-12-16 Boehringer Ingelheim International Gmbh Inhibitors of papilloma virus
WO2004113258A1 (en) 2003-06-20 2004-12-29 Shionogi & Co., Ltd. Carbon-carbon bond forming reaction
US20070010573A1 (en) 2003-06-23 2007-01-11 Xianqi Kong Methods and compositions for treating amyloid-related diseases
EP1658264A2 (en) 2003-06-23 2006-05-24 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
WO2005005382A2 (en) 2003-07-02 2005-01-20 Cytokinetics, Inc. Compounds, compositions and methods
JP4363098B2 (en) 2003-07-11 2009-11-11 三菱化学株式会社 Bisimidazopyrazinone derivatives and bisaminopyrazine derivatives
WO2005025623A2 (en) 2003-07-28 2005-03-24 Emory University Ef-24-factor vii conjugates
CA2533870A1 (en) 2003-07-30 2005-02-10 Shudong Wang Pyridinylamino-pyrimidine derivatives as protein kinase inhibitors
US7198730B2 (en) 2003-08-28 2007-04-03 E. I. Du Pont De Nemours And Company Phosphorescent material
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
WO2005026166A1 (en) 2003-09-16 2005-03-24 'chemical Diversity Research Institute', Ltd. Physiologically active composition, pharmaceutical composition, substituted 1,2-dihydro[2,7] naphthyridines, method for the production and use thereof
SI2017276T1 (en) 2003-09-22 2011-05-31 Euro Celtique Sa Phenyl-carboxamide compounds useful for treating pain
PE20050952A1 (en) 2003-09-24 2005-12-19 Novartis Ag DERIVATIVES OF ISOQUINOLINE AS INHIBITORS OF B-RAF
JP2005126586A (en) 2003-10-24 2005-05-19 Konica Minolta Holdings Inc Polymethine coloring matter, semiconductor for photoelectric conversion material, photoelectric transducer and solar battery
CA2544560C (en) 2003-11-07 2014-01-07 Taisho Pharmaceutical Co., Ltd. Processes for preparing bicyclo [3.1.0] hexane derivatives, and intermediates thereto
FR2862304A1 (en) 2003-11-14 2005-05-20 Centre Nat Rech Scient New racemic or achiral dual molecules comprising cyclic peroxide linked to antimalarially active and/or bioavailability improving residue, useful as broad-spectrum antimalarial agents
SE0303180D0 (en) 2003-11-26 2003-11-26 Astrazeneca Ab Novel compounds
US20080194574A1 (en) 2003-12-16 2008-08-14 Axxima Pharmaceuticals Ag Pyrazine Derivatives As Effective Compounds Against Infectious Diseases
US20080188527A1 (en) 2003-12-23 2008-08-07 Cashman John R Synthetic Compounds and Derivatives as Modulators of Smoking or Nicotine Ingestion and Lung Cancer
CA2554050A1 (en) 2004-02-04 2005-08-18 Neurosearch A/S Diazabicyclic aryl derivatives as cholinergic receptor modulators
DE102004005785A1 (en) 2004-02-06 2005-08-25 Bayer Cropscience Ag 2-Halogenfuryl / thienyl-3-carboxamide
WO2005079802A1 (en) 2004-02-12 2005-09-01 Merck & Co., Inc. Bipyridyl amides as modulators of metabotropic glutamate receptor-5
US7378448B2 (en) 2004-03-15 2008-05-27 Eli Lilly And Company Diphenylether amide derivatives as opioid receptor antagonists
US7596407B2 (en) 2004-03-26 2009-09-29 Solvay Pharmaceuticals, B.V. Transdermal iontophoretic delivery of piperazinyl-2(3H)-benzoxazolone compounds
AR048523A1 (en) 2004-04-07 2006-05-03 Kalypsys Inc COMPOUNDS WITH ARIL SULFONAMIDE AND SULFONYL STRUCTURE AS PPAR MODULATORS AND METHODS TO TREAT METABOLIC DISORDERS
EP2522670A1 (en) 2004-04-07 2012-11-14 Takeda Pharmaceutical Company Limited Heterocyclic CRF receptor antagonists
US20050239826A1 (en) 2004-04-14 2005-10-27 Boehringer Ingelheim International Gmbh Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds
TWI326282B (en) 2004-04-28 2010-06-21 Mitsubishi Tanabe Pharma Corp Heterocyclic compound
TWI355380B (en) 2004-05-27 2012-01-01 Nihon Nohyaku Co Ltd Substituted pyrazinecarboxanilide derivatives or s
ES2396135T3 (en) 2004-06-10 2013-02-19 Irm Llc Compounds and compositions as protein kinase inhibitors
AU2005264915A1 (en) 2004-06-16 2006-01-26 Wyeth Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase
DE602005012825D1 (en) 2004-06-16 2009-04-02 Wyeth Corp DIPHENYLIMIDAZOPYRIMIDIN AND IMIDAZOLAMINES AS B-SECRETASE INHIBITORS
JP2008504372A (en) 2004-06-18 2008-02-14 ニューロケム （インターナショナル） リミティッド Therapeutic formulations for the treatment of β-amyloid related diseases
DE102004032651A1 (en) 2004-07-06 2006-02-16 Bayer Healthcare Ag Use of substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines in the treatment of nausea and vomiting
JP5050312B2 (en) 2004-07-23 2012-10-17 コニカミノルタホールディングス株式会社 Organic electroluminescence element, display device and lighting device
DE602005008079D1 (en) 2004-07-28 2008-08-21 Hoffmann La Roche ARYL PYRIDINE DERIVATIVES AS 11-BETA-HSD1 INHIBITORS
EP1798224A1 (en) 2004-10-05 2007-06-20 Shionogi Co., Ltd. Biaryl derivative
CN101087770A (en) 2004-10-26 2007-12-12 三阶纳米技术公司 Tricyclic spacer systems for nonlinear optical devices
HUE039584T2 (en) 2004-10-29 2019-01-28 Kalypsys Inc Sulfonyl-substituted bicyclic compounds as modulators of ppar
US20080312435A1 (en) 2004-11-15 2008-12-18 Taisho Pharmaceutical Co., Ltd. Imine Compound
WO2006051937A1 (en) 2004-11-15 2006-05-18 Shionogi & Co., Ltd. Five-membered heterocyclic derivatives
CA2588776A1 (en) 2004-11-18 2006-05-26 The Institutes For Pharmaceutical Discovery, Llc Substituted amino carboxylic acids
BRPI0518476A2 (en) 2004-11-23 2008-11-18 Pfizer Prod Inc dibenzyl amine compounds and derivatives
JP2008520612A (en) 2004-11-24 2008-06-19 ノバルティス アクチエンゲゼルシャフト Combination of JAK inhibitor and at least one of Bcr-Abl, Flt-3, FAK or RAF kinase inhibitor
US20080015223A1 (en) 2004-12-03 2008-01-17 Arena Pharmaceuticals, Inc. Pyrazole Derivatives as Modulators of the 5-Ht2a Serotonin Receptor Useful for the Treatment of Disorders Related Thereto
CN101084191A (en) 2004-12-22 2007-12-05 默克公司 Process for making substituted piperidines
US7968574B2 (en) 2004-12-28 2011-06-28 Kinex Pharmaceuticals, Llc Biaryl compositions and methods for modulating a kinase cascade
WO2006070195A1 (en) 2004-12-30 2006-07-06 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of cdk, gsk and aurora kinases
WO2006080884A1 (en) 2005-01-27 2006-08-03 Astrazeneca Ab Novel biaromatic compounds, inhibitors of the p2x7-receptor
CA2596636C (en) 2005-02-07 2016-04-12 F. Hoffmann-La Roche Ag Heterocyclyl substituted phenyl methanones as inhibitors of the glycine transporter 1
KR20130089671A (en) 2005-02-11 2013-08-12 바이엘 크롭사이언스 아게 Fungicidal composition comprising a pyridylmethylbenzamide derivative and a thiazolecarboxamide derivative
WO2006088836A2 (en) 2005-02-16 2006-08-24 Schering Corporation Piperazine-piperidines with cxcr3 antagonist activity
WO2006103254A1 (en) 2005-04-01 2006-10-05 Clariant International Ltd Betaines of squaric acid for use in optical layers for optical data recording
US7820699B2 (en) 2005-04-27 2010-10-26 Hoffmann-La Roche Inc. Cyclic amines
WO2006124874A2 (en) 2005-05-12 2006-11-23 Kalypsys, Inc. Inhibitors of b-raf kinase
DE102005025315A1 (en) 2005-06-02 2006-12-14 Merck Patent Gmbh Low viscosity ionic liquids
US7312331B2 (en) 2005-06-17 2007-12-25 The Regents Of The University Of California Stable cyclic (alkyl)(amino) carbenes as ligands for transition metal catalysts
DE102005030400A1 (en) 2005-06-27 2006-12-28 Archimica Gmbh Preparation of (hetero)aryl, ethers or thioether compound, comprises cross-coupling of primary or secondary amines, alcohols or thioalcohol compound with substituted (hetero)aryl compound in the presence of Bronsted-base and catalyst
DE102005032332A1 (en) 2005-07-08 2007-01-11 Merck Patent Gmbh metal complexes
US20090176837A1 (en) 2005-07-12 2009-07-09 Sony Corporation Compounds with activity at retinoic acid receptors
WO2007011721A1 (en) 2005-07-15 2007-01-25 Kalypsys, Inc. Inhibitors of mitotic kinesin
CN100562514C (en) 2005-07-22 2009-11-25 中国科学院上海药物研究所 Substituted propion amide derivatives, Preparation Method And The Use
CN101258142A (en) 2005-08-02 2008-09-03 莱西肯医药有限公司 2-aminoaryl pyridines as protein kinases inhibitors
JP4799073B2 (en) 2005-08-04 2011-10-19 日本エンバイロケミカルズ株式会社 Microbial control agent
KR100696636B1 (en) 2005-08-18 2007-03-19 삼성에스디아이 주식회사 Photosensitizer for photovoltaic cell and photovoltaic cell prepared from the same
US8071795B2 (en) 2005-08-25 2011-12-06 Emory University HIF inhibitors
WO2007023186A1 (en) 2005-08-26 2007-03-01 Laboratoires Serono S.A. Pyrazine derivatives and use as pi3k inhibitors
US8044173B2 (en) 2005-09-13 2011-10-25 University Of Reading Asymmetric synthesis of peptides
US20090215857A1 (en) 2005-09-13 2009-08-27 Pfizer Products Inc. Therapeutic Pyrrolidines
US7732613B2 (en) 2005-09-14 2010-06-08 Bristol-Myers Squibb Company Met kinase inhibitors
DE102005045132A1 (en) 2005-09-22 2007-03-29 Archimica Gmbh Process for the preparation of 2-arylcarbonyl compounds, 2-aryl esters and 2-aryl nitriles and their heteroaromatic analogs
BRPI0616755A2 (en) 2005-09-27 2011-06-28 Novartis Ag carboxyamine compounds and methods of using them
US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
JP2007145819A (en) 2005-10-28 2007-06-14 Tanabe Seiyaku Co Ltd Pharmaceutical composition
TW200732320A (en) 2005-10-31 2007-09-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
TW200734304A (en) 2005-11-08 2007-09-16 Astellas Pharma Inc Benzene derivative or salt thereof
US7531008B2 (en) 2005-11-30 2009-05-12 L'oreal S.A. Use of at least one cationic cyanin derivative for dyeing the hair, composition containing it, process for treating keratin fibers using the composition, and device therefor
CN101370776A (en) 2005-12-01 2009-02-18 伊兰医药品股份有限公司 5-(arylsulfonyl)-pyrazolopiperidines
US20090182142A1 (en) 2005-12-02 2009-07-16 Shigeru Furukubo Aromatic Compound
JP2007161674A (en) 2005-12-16 2007-06-28 Tanabe Seiyaku Co Ltd Piperidine compound and its production method
WO2007073855A1 (en) 2005-12-23 2007-07-05 Bayer Healthcare Ag Use of adenosine a1 receptor agonists for the protection of renal cells against toxic effects caused by aminoglycosides during treatment of infectious diseases
US7855291B2 (en) 2005-12-29 2010-12-21 Lexicon Pharmaceuticals, Inc. Process for the preparation of substituted phenylalanines
EP1968579A1 (en) 2005-12-30 2008-09-17 Astex Therapeutics Limited Pharmaceutical compounds
DE102006000651A1 (en) 2006-01-03 2007-07-12 Degussa Gmbh Preparation of ionic liquids and resins
DE102006000649A1 (en) 2006-01-03 2007-07-05 Degussa Gmbh Universally-applicable composition, e.g. for pigment paste, coating material or ink, contains pigment or filler and a film-forming dispersant comprising ketone, ketone-aldehyde or urea-aldehyde resin and ionic liquid
FR2896798A1 (en) 2006-01-27 2007-08-03 Sanofi Aventis Sa SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
HUP0600101A2 (en) 2006-02-09 2007-09-28 Univ Szegedi Resolution process for the preparation of cyclic beta-amino acids esters there of
US8227093B2 (en) 2006-02-11 2012-07-24 Samsung Mobile Display Co., Ltd. Cyclometalated transition metal complex and organic electroluminescence device using the same
CN101384586A (en) * 2006-02-14 2009-03-11 诺华公司 Pi-3 kinase inhibitors and methods of their use
DE102006009813A1 (en) 2006-03-01 2007-09-06 Bayer Healthcare Ag Use of A2b / A1 receptor agonists to modulate lipid levels
EP1996577B1 (en) 2006-03-21 2016-02-10 Merck Sharp & Dohme Corp. Heterocyclic substituted pyridine compounds with cxcr3 antagonist activity
US7872031B2 (en) 2006-03-22 2011-01-18 Vertex Pharmaceuticals Incorporated c-MET protein kinase inhibitors
JP5385125B2 (en) 2006-03-22 2014-01-08 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Inhibitors of the interaction between MDM2 and p53
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2007113258A1 (en) 2006-04-03 2007-10-11 Glaxo Group Limited Azabicyclo [3. 1. o] hexane derivatives as modulators of dopamine d3 receptors
MX2008013237A (en) 2006-04-14 2009-03-06 Merck & Co Inc Substituted imidazole 4-carboxamides as cholecystokinin-1 receptor modulators.
EP2010179B1 (en) 2006-04-14 2010-07-07 Merck Sharp & Dohme Corp. Substituted imidazole 4-carboxamides as cholecystokinin-1 receptor modulators
CN101058577A (en) 2006-04-18 2007-10-24 中国科学院化学研究所 1,4-Dihydropyridine compound and preparation method thereof
EP2010523A1 (en) 2006-04-27 2009-01-07 Glaxo Group Limited Spirocompounds useful as modulators for dopamine d3 receptors
CN101636154B (en) 2006-04-27 2011-12-14 塞诺菲-安万特德国有限公司 Inhibitors of the TASK-1 and TASK-3 ion channels
WO2007129664A1 (en) 2006-05-02 2007-11-15 National University Corporation Nagoya University Chiral tetradentate ligand for asymmetric catalytic action and use thereof
ITMI20060895A1 (en) 2006-05-08 2007-11-09 Kemon S P A PRIMARY INTERMEDIATES FOR OXIDATIVE HAIR COLORING
DE102006025316A1 (en) 2006-05-31 2007-12-06 Bayer Healthcare Ag Isoindolin-1-one, isoindolin-3-one and isoindoline-1,3-dione derivatives and their use
ES2340093T3 (en) 2006-06-22 2010-05-28 Biovitrum Ab (Publ) PIRAZINE AND PIRIDINE DERIVATIVES AS INHIBITORS OF CINASA MNK.
US20080280891A1 (en) 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
AU2007265373B2 (en) 2006-06-29 2013-02-21 Atnx Spv, Llc Biaryl compositions and methods for modulating a kinase cascade
DK2041071T3 (en) 2006-06-29 2014-09-01 Kinex Pharmaceuticals Llc BIARLYL COMPOSITIONS AND PROCEDURES FOR MODULATING A CHINA CASE
DK2034839T3 (en) 2006-06-30 2017-12-04 Sloan-Kettering Institute For Cancer Res TREATMENT OF NEURODEGENERATIVE DISEASES BY INHIBITION OF HSP90
CA2655629A1 (en) 2006-07-04 2008-01-10 Astrazeneca Ab New pyridine analogues
WO2008007900A1 (en) 2006-07-11 2008-01-17 Daewoong Pharmaceutical Co., Ltd. Novel biaryl benzoimidazole derivatives and pharmaceutical composition comprising the same
ITMI20061368A1 (en) 2006-07-14 2008-01-15 Acraf 2-ARILINDOLIC COMPOUND REPLACED IN POSITION 5, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AS WELL AS COMPOUNDS AND INTERMEDIATE PROCEDURES TO PREPARE IT
MX2009000577A (en) 2006-07-14 2009-03-09 Schering Corp Heterocyclic substituted piperazine compounds with cxcr3 antagonist activity.
MX2009001279A (en) 2006-08-03 2009-02-11 Tufts College Non-flushing niacin analogues, and methods of use thereof.
EP1900727A1 (en) 2006-08-30 2008-03-19 Cellzome Ag Aminopyridine derivatives as kinase inhibitors
JP2010504295A (en) 2006-09-21 2010-02-12 ノバルティス アーゲー Pyrrole derivatives useful for the treatment of cytokine-mediated diseases
KR100932093B1 (en) 2006-09-27 2009-12-16 주식회사종근당 Benzophenone Derivatives Useful as Inhibitors of Microtubule Formation
GB0619342D0 (en) 2006-09-30 2006-11-08 Vernalis R&D Ltd New chemical compounds
WO2008044713A1 (en) 2006-10-10 2008-04-17 Nihon Nohyaku Co., Ltd. Substituted pyridinecarboxanilide derivative or salt thereof, and agricultural or horticultural agent, and use thereof
DE102006048042A1 (en) 2006-10-11 2008-04-17 Bayer Healthcare Ag Acylaminoimidazoles and acylaminothiazoles
DE102006048924A1 (en) 2006-10-17 2008-04-24 Bayer Healthcare Ag Acylaminopyrazole
US7820605B2 (en) 2006-10-27 2010-10-26 Chevron Oronite Company Llc Lubricating oil additive composition and method of making the same
WO2008052733A1 (en) 2006-10-30 2008-05-08 Novartis Ag Imidazopyridazines as pi3k lipid kinase inhibitors
KR101146875B1 (en) 2006-11-01 2012-05-16 에스케이이노베이션 주식회사 Transition metal catalytic systems and methods for preparing ethylene homopolymers or copolymers of ethylene and olefins using the same
JP2009023986A (en) 2006-11-08 2009-02-05 Pharma Ip Biaryl derivative as anticancer agent
US8519130B2 (en) 2006-12-08 2013-08-27 Universal Display Corporation Method for synthesis of iriduim (III) complexes with sterically demanding ligands
WO2008073480A1 (en) 2006-12-11 2008-06-19 Irm Llc Compounds and compositions as kinase inhibitors
US8466163B2 (en) 2006-12-11 2013-06-18 Bionomics Limited Furo[2,3-d]pyrimidines and related compounds and methods for treating disease states by inhibiting tubulin polymerization
GB0624689D0 (en) 2006-12-11 2007-01-17 Glaxo Group Ltd Novel fluorescent kinase ligands and methods employing the same
UA99270C2 (en) 2006-12-12 2012-08-10 Лексикон Фармасьютикалз, Инк. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use
FR2910298A1 (en) 2006-12-20 2008-06-27 Oreal Composition for coloring keratinic fibers, especially hair, comprises a fluorescent dye or optical brightener and two silicones that react together by hydrosilylation, condensation or crosslinking
GB0625659D0 (en) 2006-12-21 2007-01-31 Cancer Rec Tech Ltd Therapeutic compounds and their use
TW200840566A (en) 2006-12-22 2008-10-16 Esteve Labor Dr Heterocyclyl-substituted-ethylamino-phenyl derivatives, their preparation and use as medicaments
EP1938686A1 (en) 2006-12-29 2008-07-02 Bayer CropScience AG Substituted 1-(3-pyridinyl)pyrazol-4-yl-acetic acids, process for their preparation and their use as herbicide and plant growth regulator.
FR2911876B1 (en) 2007-01-29 2009-03-06 Rhodia Recherches & Tech NOVEL ORGANOMETALLIC MIXED COMPLEXES BASED ON ALKYLLAMINOCYCLICALLY BASED CARBENES.
CA2677096A1 (en) 2007-01-31 2008-08-07 Vertex Pharmaceuticals Incorporated Kinase inhibitors
US20080269241A1 (en) 2007-02-15 2008-10-30 Darin Allen Bicyclic aminopropyl tetrahydro-pyrazolo-pyridine modulators of cathepsin s
EP1975159A1 (en) 2007-03-27 2008-10-01 Bayer Schering Pharma Aktiengesellschaft 2,3,4,9-Tetrahydro-1H-carbazoles
EP1974729A1 (en) 2007-03-28 2008-10-01 Santhera Pharmaceuticals (Schweiz) AG Substituted imidazopyridine derivates as melanocortin- 4 receptor antagonists
KR101538811B1 (en) 2007-04-03 2015-07-22 이 아이 듀폰 디 네모아 앤드 캄파니 substituted benzene fungicides
US8039505B2 (en) 2007-04-11 2011-10-18 University Of Utah Research Foundation Compounds for modulating T-cells
US7482492B2 (en) 2007-04-12 2009-01-27 Xerox Corporation Cost effective method for synthesis of triarylamine compounds
US20100256147A1 (en) 2007-04-13 2010-10-07 Hangauer Jr David G Biaryl acetamide derivatives as modulators of the kinase cascade for the treatment of hearing loss, osteoporosis and cell proliferation disorders
ES2366743T3 (en) 2007-04-27 2011-10-25 Agfa Graphics N.V. PRECURSOR OF LITHOGRAPHIC PRINT PLATE.
US20100130450A1 (en) 2007-05-03 2010-05-27 Northeastern University Methods of Treating Fungal Infections
US8263585B2 (en) 2007-05-04 2012-09-11 Novartis Ag Organic compounds
TWI371445B (en) 2007-05-17 2012-09-01 Lg Chemical Ltd New anthracene derivatives and organic electronic device using the same
PE20090717A1 (en) * 2007-05-18 2009-07-18 Smithkline Beecham Corp QUINOLINE DERIVATIVES AS PI3 KINASE INHIBITORS
TW200846319A (en) 2007-05-28 2008-12-01 China Petrochemical Dev Corp Method for preparing carbonate diester
EP1997493A1 (en) 2007-05-28 2008-12-03 Laboratorios del Dr. Esteve S.A. Combination of a 5-HT7 receptor ligand and an opioid receptor ligand
WO2008150899A1 (en) 2007-05-29 2008-12-11 Emory University Combination therapies for treatment of cancer and inflammatory diseases
EP2164923A4 (en) 2007-05-30 2010-09-01 Cheil Ind Inc Organic photoelectric device and material used therein
JP2009007342A (en) 2007-06-01 2009-01-15 Mitsubishi Tanabe Pharma Corp Medicinal composition
EP2155711A1 (en) 2007-06-05 2010-02-24 Sanofi-Aventis Substituted benzoylamino-indan-2-carboxylic acids and related compounds
JP5104060B2 (en) 2007-06-25 2012-12-19 コニカミノルタホールディングス株式会社 ORGANIC ELECTROLUMINESCENT ELEMENT MATERIAL, ORGANIC ELECTROLUMINESCENT ELEMENT, DISPLAY DEVICE AND LIGHTING DEVICE
AU2008268409B2 (en) 2007-06-26 2013-12-05 Lexicon Pharmaceuticals, Inc. Compositions comprising tryptophan hydroxylase inhibitors
GB0713259D0 (en) 2007-07-09 2007-08-15 Astrazeneca Ab Pyrazine derivatives 954
AR067585A1 (en) 2007-07-19 2009-10-14 Schering Corp AMIDAS HETEROCICLICAL COMPOUNDS AS INHIBITORS OF PROTEINCINASE
MX2010001020A (en) 2007-07-26 2010-03-01 Novartis Ag Organic compounds.
TWI388566B (en) 2007-08-29 2013-03-11 Nat Univ Tsing Hua Transition metal complexes with carbene ligands and their application
WO2009039181A2 (en) 2007-09-17 2009-03-26 State Of Oregon Acting By & Through The State Board Of Higher Education On Behalf Of Or. State Univ. Sulfonamide-based organocatalysts and method for their use
US20100227845A1 (en) 2007-10-18 2010-09-09 Zhicai Wu Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases
FR2922550B1 (en) 2007-10-19 2009-11-27 Sanofi Aventis NOVEL 6-ARYL / HETEROALKYLOXY BENZOTHIAZOLE AND BENZIMIDAZOLE DERIVATIVES, APPLICATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS CMET INHIBITORS
EP2211620B1 (en) 2007-10-25 2013-12-25 Merck Sharp & Dohme Corp. 3-PYRAZIN SUBSTITUTED PYRROLO[2,3-b]PYRIDINES AS JANUS KINASE INHIBITORS FOR THE TREATMENT OF CANCER DISEASES
KR100957620B1 (en) 2007-11-01 2010-05-13 제일모직주식회사 Material for organic photoelectric device, and organic photoelectric device thereby
US7960547B2 (en) 2007-12-03 2011-06-14 Chien-Hong Cheng Transition metal complexes with carbene ligands and their application
CN101450939B (en) 2007-12-05 2013-06-19 沈阳药科大学 Novel benzimidazoles compounds
MX2010006203A (en) 2007-12-07 2010-06-25 Novartis Ag Pyrazole derivatives and use thereof as inhibitors of cyclin dependent kinases.
JP2009185020A (en) 2008-01-11 2009-08-20 Ishihara Sangyo Kaisha Ltd Pyridylamidine derivative or salt thereof, and agricultural or horticultural fungicide containing the same as active ingredient
GB0801199D0 (en) 2008-01-23 2008-02-27 Acal Energy Ltd Fuel cells
JP2011510033A (en) 2008-01-25 2011-03-31 シンジェンタ パーティシペーションズ アクチェンゲゼルシャフト Compound
US8273744B2 (en) 2008-02-04 2012-09-25 Mercury Therapeutics, Inc. AMPK modulators
JP2011512357A (en) 2008-02-15 2011-04-21 メルク・シャープ・エンド・ドーム・コーポレイション Fused pyridone M1 receptor positive allosteric modulator
CN102007126A (en) 2008-02-22 2011-04-06 Irm责任有限公司 Compounds and compositions as modulators of gpr119 activity
GB0804067D0 (en) 2008-03-04 2008-04-09 Syngenta Participations Ag Chemical compounds
EP2262767A1 (en) 2008-03-11 2010-12-22 NeuroSearch A/S Novel triaryl derivatives useful as modulators of nicotinic acetylcholine receptors
GB0804702D0 (en) 2008-03-13 2008-04-16 Amura Therapeutics Ltd Compounds
GB0804701D0 (en) 2008-03-13 2008-04-16 Amura Therapeutics Ltd Compounds
JP5509104B2 (en) 2008-03-14 2014-06-04 エグゼリクシス， インコーポレイテッド Azabicyclo [3.2.1] octyl derivatives as 11β-HSD1 modulators
US8268834B2 (en) 2008-03-19 2012-09-18 Novartis Ag Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme
FR2928922B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis DERIVATIVES OF POLYSUBSTITUTED 2-ARYL-6-PHENYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
US8236446B2 (en) 2008-03-26 2012-08-07 Ada Technologies, Inc. High performance batteries with carbon nanomaterials and ionic liquids
US8415479B2 (en) 2008-03-31 2013-04-09 Renascience Co., Ltd. Inhibitor of plasminogen activator inhibitor-1
GB2472554B (en) 2008-05-05 2012-12-05 Ada Technologies Inc High performance carbon nanocomposites for ultracapacitors
KR101649482B1 (en) 2008-05-05 2016-08-19 사노피 Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals
FR2930939B1 (en) 2008-05-09 2010-07-30 Sanofi Aventis PYRROLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
US8153634B2 (en) 2008-05-29 2012-04-10 Kowa Company, Ltd. Carbinol derivatives having cyclic linker
CN101591332B (en) 2008-05-30 2014-04-16 莱西肯医药有限公司 Compound based on 4-phenyl-6-(2, 2, 2-trifluoro-1-phenylethoxy) pyridine and application method thereof
ATE552255T1 (en) 2008-06-05 2012-04-15 Glaxo Group Ltd 4-AMINOINDAZOLES
WO2009148052A1 (en) 2008-06-05 2009-12-10 旭化成ファーマ株式会社 Sulfonamide compound and application thereof
JP2011526294A (en) 2008-06-25 2011-10-06 エンビボ ファーマシューティカルズ インコーポレイテッド Disubstituted phenyl compounds as phosphodiesterase 10 inhibitors
KR101015858B1 (en) 2008-06-26 2011-02-23 제일모직주식회사 Organic compound, and organic photoelectric device including the same
TW201002202A (en) 2008-06-27 2010-01-16 Du Pont Fungicidal pyridines
CN101619056B (en) 2008-07-02 2013-07-17 石药集团中奇制药技术（石家庄）有限公司 Benzothiophene alkanol piperazine derivatives and use thereof as antidepressant medicaments
TWI436973B (en) 2008-08-07 2014-05-11 China Petrochemical Dev Corp Liquid-phase oxidation method for hydrocarbons
JP2012500223A (en) 2008-08-15 2012-01-05 ローカス ファーマスーティカルズ，インコーポレイテッド Urea derivatives as MAP kinase inhibitors
JP5412519B2 (en) 2008-09-02 2014-02-12 ノバルティス アーゲー Picolinamide derivatives as kinase inhibitors
WO2010027583A1 (en) 2008-09-03 2010-03-11 Universal Display Corporation Phosphorescent materials
UA104147C2 (en) 2008-09-10 2014-01-10 Новартис Аг Pyrrolidine dicarboxylic acid derivative and use thereof in the treatment of proliferative diseases
US20110294853A1 (en) 2008-09-12 2011-12-01 Benjamin Pelcman Bis Aromatic Compounds for Use in the Treatment of Inflammation
EP2346825A2 (en) 2008-09-18 2011-07-27 Evotec AG Modulators of p2x3 receptor activity
EP2168965A1 (en) 2008-09-25 2010-03-31 Santhera Pharmaceuticals (Schweiz) AG Substituted imidazopyridine, imidazopyrazine, imidazopyridazine and imidazopyrimidine derivatives as melanocortin-4 receptor antagonists
US20120022070A1 (en) 2008-10-06 2012-01-26 Emory University Heat Shock Protein 90 Inhibitors, Methods Of Preparing Same, And Methods For Their Use
JP5775819B2 (en) 2008-10-09 2015-09-09 ハワード ヒューズ メディカル インスティチュート Novel chimeric ligand-gated ion channel and method of use thereof
US8435911B2 (en) 2008-10-16 2013-05-07 Basell Polyolefine Gmbh Hybrid catalyst composition for polymerization of olefins
FR2937262B1 (en) 2008-10-17 2010-11-05 Inst Francais Du Petrole PROCESS FOR THE PREPARATION OF A CATALYTIC COMPOSITION FOR DIMERISATION, CO-DIMERIZATION AND OLIGOMERIZATION OF OLEFINS
JP2012506381A (en) 2008-10-21 2012-03-15 バーテックス ファーマシューティカルズ インコーポレイテッド c-MET protein kinase inhibitor
RU2011120822A (en) 2008-10-24 2012-11-27 Лексикон Фармасьютикалз, Инк. METHOD FOR PRODUCING SUBSTITUTED PHENYLALANINES
CN102264721B (en) 2008-11-10 2015-12-09 沃泰克斯药物股份有限公司 As the compound of ATR kinase inhibitor
WO2010056992A1 (en) 2008-11-13 2010-05-20 The Trustees Of Columbia University In The City Of New York Methods of preventing and treating low bone mass diseases
TW201028399A (en) * 2008-11-27 2010-08-01 Shionogi & Co Pyrimidine derivative and pyridine derivative both having pi3k inhibitory activity
WO2010065333A1 (en) 2008-12-01 2010-06-10 Lexicon Pharmaceuticals, Inc. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds for the treatment of osteoporosis
JP2010143829A (en) 2008-12-16 2010-07-01 Dainippon Sumitomo Pharma Co Ltd New imidazoquinoline derivative
EP2370409A1 (en) 2008-12-18 2011-10-05 E. I. du Pont de Nemours and Company Continuous liquid-phase process for the synthesis of diaminopyridines from glutaronitriles
DE102009055828A1 (en) 2008-12-19 2010-07-01 Merck Patent Gmbh Preparing metal coated particles, useful e.g. in lacquers, colors, inks, pigment mixtures, comprises electrochemical metal deposition of metals on the particle substrate, whose surface is electrically conductive or semi-conductive
RS56995B1 (en) 2008-12-19 2018-05-31 Vertex Pharma Pyrazine derivatives useful as inhibitors of atr kinase
TW201024259A (en) 2008-12-24 2010-07-01 China Petrochemical Dev Corp Method for preparing organic carboxylic acid ester
CN101781200B (en) 2009-01-20 2013-04-03 中国石油化学工业开发股份有限公司 Manufacturing method of organic carboxylic ester
WO2010091384A2 (en) 2009-02-09 2010-08-12 Georgetown University Cadherin-11 inhibitors and methods of use thereof
UA107188C2 (en) 2009-02-11 2014-12-10 CARBOXAMID DERIVATIVES OF QUINASOLINES OR QUINOLINES AND PHARMACEUTICAL COMPOSITION THEREOF
WO2010100475A1 (en) 2009-03-02 2010-09-10 Astrazeneca Ab Hydroxamic acid derivatives as gram-negative antibacterial agents
CN101513584B (en) 2009-03-04 2011-11-09 中国科学院过程工程研究所 New method for desulfurization by oxidation based on alkaline ionic liquid catalyst
WO2010111573A1 (en) 2009-03-27 2010-09-30 Abbott Laboratories Compounds as cannabinoid receptor ligands
KR20120034613A (en) * 2009-04-16 2012-04-12 센트로 내셔널 드 인베스티가시오네스 온콜로지카스 (씨엔아이오) Imidazopyrazines for use as kinase inhibitors
UY32582A (en) * 2009-04-28 2010-11-30 Amgen Inc 3 KINASE PHOSPHINOSITI INHIBITORS AND / OR MAMMAL OBJECTIVE
JP2012162460A (en) 2009-05-27 2012-08-30 Nippon Soda Co Ltd Nitrogen-containing heteroaryl derivative and germicide for agriculture and horticulture
WO2010138901A1 (en) 2009-05-29 2010-12-02 Biogen Idec Ma Inc Carboxylic acid-containing compounds, derivatives thereof, and related methods of use
US20100331315A1 (en) 2009-06-18 2010-12-30 Mustapha Haddach Rhodanines and related heterocycles as kinase inhibitors
WO2010150204A1 (en) 2009-06-25 2010-12-29 Institut Univ. De Ciència I Tecnologia, S.A. N-(2-oxo-1-phenylpiperidin-3-yl) sulfonamides for the identification of biological and pharmacological activity
ES2354550B1 (en) 2009-06-26 2011-11-15 Institut Univ. De Ciència I Tecnologia, S.A. LIBRARY OF N- (1-PHENYL-2-OXO-3-PIPERIDIL) SULFONAMIDS FOR THE DISCOVERY OF DRUGS.
ES2354551B1 (en) 2009-07-01 2011-11-15 Institut Univ. De Ciencia I Tecnologia S.A. LIBRARIES OF N- (1-PHENYL-2-OXO-3-PIPERIDIL) SULFONAMIDS FOR THE IDENTIFICATION OF BIOLOGICAL AND PHARMACOLOGICAL ACTIVITY.
UA102916C2 (en) 2009-07-02 2013-08-27 Кемфарм, Інк. Composition based on conjugates of hydrocodone with benzoic acid, benzoic acid or heteroaryl carboxylic acid derivatives, prodrugs and method for treatment of abuses
JP2014501097A (en) 2009-07-06 2014-01-20 アルナイラム ファーマシューティカルズ， インコーポレイテッド Composition and method for enhancing production of biological material
CA2767231A1 (en) 2009-07-06 2011-01-13 Alnylam Pharmaceuticals, Inc. Cell-based bioprocessing
WO2011005842A1 (en) 2009-07-09 2011-01-13 Gilead Sciences, Inc. Anti-rsv compounds
AR077468A1 (en) 2009-07-09 2011-08-31 Array Biopharma Inc PIRAZOLO COMPOUNDS (1,5-A) PYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS
JP4590020B1 (en) 2009-07-31 2010-12-01 富士フイルム株式会社 Charge transport material and organic electroluminescent device
JP4599469B1 (en) 2009-08-31 2010-12-15 富士フイルム株式会社 Organic electroluminescent element material and organic electroluminescent element
FR2949465B1 (en) 2009-09-01 2011-08-12 Pf Medicament CHROMIUM DERIVATIVES, PROCESS FOR PREPARING THEM AND THERAPEUTIC APPLICATIONS THEREOF
WO2011028638A1 (en) 2009-09-04 2011-03-10 Schering Corporation Modulators of cell cycle checkpoints and their use in combination with checkpoint kinase inhibitors
WO2011032034A2 (en) 2009-09-10 2011-03-17 University Of Idaho Nucleobase-functionalized conformationally restricted nucleotides and oligonucleotides for targeting nucleic acids
EP2477976A4 (en) 2009-09-18 2013-03-13 Boehringer Ingelheim Int Quinazolinone derivatives as viral polymerase inhibitors
WO2011036461A1 (en) 2009-09-24 2011-03-31 Centro Nacional De Investigaciones Oncόlogicas (Cnio) Fused imidazo [3, 2 - d] pyrazines as pi3 kinase inhibitors
DE102009043260A1 (en) 2009-09-28 2011-04-28 Merck Patent Gmbh Pyridinyl-imidazolone derivatives
CA2777041A1 (en) 2009-10-06 2011-04-14 Bristol-Myers Squibb Company Pyrrolidine gpr40 modulators
EP2490530A4 (en) 2009-10-22 2014-01-22 Univ Washington Compounds and methods for treating bacterial infections
WO2011049150A1 (en) 2009-10-22 2011-04-28 Sumitomo Chemical Company, Limited Pyrone compound and its use for pest control
CN101712809A (en) 2009-10-30 2010-05-26 上海拓引数码技术有限公司 Organic dyestuff and preparation method thereof and recordable optical information recording medium containing organic dyestuff
US8759377B2 (en) 2009-11-23 2014-06-24 Vanderbilt University Substituted dioxopiperidines and dioxopyrrolidines as MGLUR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
AU2010328336B2 (en) 2009-12-07 2017-03-02 Arbutus Biopharma Corporation Compositions for nucleic acid delivery
WO2011072064A1 (en) 2009-12-08 2011-06-16 Array Biopharma Inc. S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors
EP2511269A4 (en) 2009-12-11 2013-04-24 Shionogi & Co Fused heterocyclic compound having amino group
AU2010333338A1 (en) 2009-12-14 2012-08-02 Merck Patent Gmbh Sphingosine kinase inhibitors
WO2011081945A2 (en) 2009-12-14 2011-07-07 Cornell University Activation and activators of sirt6
WO2011081937A1 (en) 2009-12-15 2011-07-07 Gilead Sciences, Inc. Corticosteroid-beta-agonist-muscarinic antagonist compounds for use in therapy
US20110190267A1 (en) 2010-01-05 2011-08-04 Shire Pharmaceuticals, Inc. Prodrugs of opioids and uses thereof
WO2011082488A1 (en) 2010-01-06 2011-07-14 British Columbia Cancer Agency Branch Bisphenol derivative therapeutics and methods for their use
CN102812006B (en) 2010-01-18 2016-01-20 Mmv疟疾药物投资公司 Novel antimalaria reagent
DK2528901T3 (en) 2010-01-27 2015-08-17 Boehringer Ingelheim Int Pyrazole compounds as CRTH2 antagonists.
JP5675850B2 (en) 2010-02-05 2015-02-25 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Hetaryl- [1,8] naphthyridine derivatives
CN103038228A (en) 2010-03-16 2013-04-10 安万特药物公司 Substituted pyrimidines as prostaglandin D2 receptor antagonists
EA201290957A1 (en) 2010-04-07 2013-04-30 Ф.Хоффманн-Ля Рош Аг PYRAZOL-4-ILHETEROCYCLILKARBOXAMIDE COMPOUNDS AND METHODS OF THEIR APPLICATION
ES2645367T3 (en) 2010-04-16 2017-12-05 Athenex, Inc. Compositions and methods for cancer prevention and treatment
FR2959944B1 (en) 2010-05-12 2012-06-08 Inst Francais Du Petrole ABSORBENT SOLUTION CONTAINING PYRIDINE-DERIVED DEGRADATION INHIBITOR AND METHOD FOR ABSORPTION OF ACIDIC COMPOUNDS CONTAINED IN GASEOUS EFFLUENT
MX2012013082A (en) 2010-05-12 2013-05-09 Vertex Pharma 2 -aminopyridine derivatives useful as inhibitors of atr kinase.
EP2568984A1 (en) 2010-05-12 2013-03-20 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
JP5702855B2 (en) 2010-05-13 2015-04-15 アムジエン・インコーポレーテツド Nitrogen heterocyclic compounds useful as PDE10 inhibitors
TWI428343B (en) 2010-05-14 2014-03-01 Nat Univ Tsing Hua Thiocyanate-free ru(ii) sensitizers and dye-sensitized solar cells
EP2576576A4 (en) 2010-05-28 2014-03-05 Univ Mcgill Heterocyclyl-pyridinyl-based biphosphonic acid, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof
US8889768B2 (en) 2010-06-11 2014-11-18 Basf Se Laser-transparent PBT with organic additives
US8716487B2 (en) 2010-06-22 2014-05-06 Basf Se Process for preparing 4-hydroxypyridines
UY33469A (en) 2010-06-29 2012-01-31 Irm Llc Y Novartis Ag COMPOSITIONS AND METHODS TO MODULATE THE WNT SIGNALING ROAD
KR20130131293A (en) 2010-07-05 2013-12-03 메르크 파텐트 게엠베하 Bipyridyl derivatives useful for the treatment of kinase - induced diseases
ES2526981T3 (en) 2010-07-12 2015-01-19 Pfizer Limited N-sulfonylbenzamides as voltage dependent sodium channel inhibitors
CA2804351A1 (en) 2010-07-12 2012-01-19 Pfizer Limited Chemical compounds
US8946434B2 (en) 2010-07-16 2015-02-03 N30 Pharmaceuticals, Inc. Dihydropyridin-2(1H)-one compound as S-nirtosoglutathione reductase inhibitors and neurokinin-3 receptor antagonists
JP5587701B2 (en) 2010-08-06 2014-09-10 日本エンバイロケミカルズ株式会社 Microbicide control agent for laboratory water circulation / storage device, and microorganism control method for laboratory water circulation / storage device
JP5876051B2 (en) 2010-09-08 2016-03-02 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Indazole derivatives for use in the treatment of influenza virus infection
EP2617715A4 (en) 2010-09-17 2014-02-26 Taisho Pharmaceutical Co Ltd Glycine transporter inhibitor
ES2379919B1 (en) 2010-10-06 2013-03-19 Consejo Superior De Investigaciones Científicas (Csic) SYNTHESIS OF BICYCLIC PIRIDONAS CONTAINING THE HIDEROCYCLIC SYSTEM OF IMIDAZOL (1,2-a) PIRIDINE, FROM 2-AMINO-6- (PROP-2-IN-1-IL AMINO) PIRIDINES.
WO2012074869A1 (en) 2010-11-24 2012-06-07 Exelixis, Inc. Benzoxazepines as inhibitors of pi3k/mtor and methods of their use and manufacture
GB201020161D0 (en) 2010-11-26 2011-01-12 Almac Discovery Ltd Pharmaceutical compounds
IT1402842B1 (en) 2010-11-30 2013-09-27 Annunziato 7-NITRO-5-PHENYL-1 (PYRROLIDIN-1-ILMETHYL) -1H-BENZO [E] [1,4] DIAZEPIN-2 (3H) -ONE AND OTHER COMPOUNDS BENZODIAZEPINE DERIVATIVES.
KR101728898B1 (en) 2010-12-07 2017-04-21 광주과학기술원 Novel Hydrazine Derivatives and Uses Thereof
DE102010054892A1 (en) 2010-12-17 2012-06-21 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Producing a polyester, useful to produce molded bodies, comprises carrying out dehydration or partial condensation of hydroxycarboxylic acid and dicarboxylic acid, adding zinc containing catalyst and performing polycondensation
CN102125875B (en) 2011-01-20 2012-09-05 郑州大学 Application of cyclopalladated ferrocenylimine-phosphine adduct in synthesis of asymmetric biaryl compound
IT1404379B1 (en) 2011-02-11 2013-11-22 Lembo HETEROCYCLES WITH ANTI-HYPERTENSIVE ACTIVITY
WO2012108881A1 (en) 2011-02-11 2012-08-16 Universal Display Corporation Organic light emitting device and materials for use in same
WO2012108879A1 (en) 2011-02-11 2012-08-16 Universal Display Corporation Organic light emitting device and materials for use in same
WO2012112958A2 (en) 2011-02-19 2012-08-23 The Broad Institute, Inc High-throughput assays to probe leukemia within the stromal niche
US20140171525A1 (en) 2011-02-21 2014-06-19 Honeywell International Inc. Polyurethane foam premixes containing halogenated olefin blowing agents and foams made from same
CA2826773C (en) 2011-02-24 2019-07-16 Emory University Jab1 blocking compositions for ossification and methods related thereto
WO2012121939A2 (en) 2011-03-04 2012-09-13 Locus Pharmaceuticals, Inc. Aminopyrazine compounds
WO2012125629A1 (en) * 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
CN103097367B (en) 2011-04-02 2014-12-03 中国人民解放军军事医学科学院毒物药物研究所 Phenylpropionic acid compound, preparation method therefor and medicinal use thereof
KR20140027974A (en) 2011-04-05 2014-03-07 버텍스 파마슈티칼스 인코포레이티드 Aminopyrazine compounds useful as inhibitors of tra kinase
KR101442644B1 (en) 2011-04-12 2014-09-19 주식회사 종근당 Cycloalkenyl Aryl Derivatives for ＣＥＴＰ Inhibitor
WO2012151355A1 (en) 2011-05-03 2012-11-08 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US20120289481A1 (en) 2011-05-13 2012-11-15 O'neil Jennifer Compositions and methods for treating cancer
EP2524918A1 (en) 2011-05-19 2012-11-21 Centro Nacional de Investigaciones Oncológicas (CNIO) Imidazopyrazines derivates as kinase inhibitors
US8598161B2 (en) 2011-05-24 2013-12-03 Bristol-Myers Squibb Company Compounds for the reduction of beta-amyloid production
EP2714698B1 (en) 2011-05-31 2016-11-09 Merck Patent GmbH Compounds containing hydrido-tricyano-borate anions
AR086653A1 (en) 2011-06-03 2014-01-15 Bristol Myers Squibb Co COMPOUNDS FOR REDUCTION OF PRODUCTION OF B-AMYLOID
CN102260218B (en) 2011-06-07 2013-05-08 北京理工大学 Method for synthesizing aminopyrazine perfumes
JP2014517079A (en) 2011-06-22 2014-07-17 バーテックス ファーマシューティカルズ インコーポレイテッド Compounds useful as ATR kinase inhibitors
WO2012177639A2 (en) 2011-06-22 2012-12-27 Alnylam Pharmaceuticals, Inc. Bioprocessing and bioproduction using avian cell lines
JP2014520161A (en) 2011-06-22 2014-08-21 バーテックス ファーマシューティカルズ インコーポレイテッド Compounds useful as ATR kinase inhibitors
AR086745A1 (en) 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-DIAMINO-6-CHLORINE-N- (N- (4- (4- (2- (HEXIL (2,3,4,5,6-PENTAHYDROXIHEXIL)) AMINO) ETOXI) PHENYL) BUTIL) CARBAMIMIDOIL) PIRAZINA -2-CARBOXAMIDE
CN102850328B (en) 2011-07-01 2014-12-24 苏州东南药业股份有限公司 Pyridine chemical, its preparation method, and pharmaceutical composition containing the chemical and application thereof
KR101502500B1 (en) 2011-07-01 2015-03-16 주식회사 엘지화학 Nonaqueous electrolyte and lithium secondary battery using the same
EP2543673A1 (en) 2011-07-08 2013-01-09 cynora GmbH Copper(I) complexes for optoelectronic devices
JP2014521682A (en) 2011-08-05 2014-08-28 アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー Aminochroman, aminothiochroman and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
AU2012293417A1 (en) 2011-08-10 2013-05-02 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
CA2843083A1 (en) 2011-08-12 2013-02-21 Basf Se Anthranilamide compounds and their use as pesticides
JP2014522872A (en) 2011-08-12 2014-09-08 ビーエーエスエフ ソシエタス・ヨーロピア N-thio-anthranilamide compounds and their use as pesticides
BR112014003382B1 (en) 2011-08-15 2022-03-15 University Of Utah Research Foundation (E)-N-(1-PHENYLETHYLIDENE) ANALOGS SUBSTITUTED BENZOHYDRAZIDE AS HISTONE DEMETHYLASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
JP2014524432A (en) 2011-08-18 2014-09-22 ビーエーエスエフ ソシエタス・ヨーロピア Carbamoylmethoxybenzamide and carbamoylmethylthiobenzamide and carbamoylmethylaminobenzamide for combating harmful invertebrates
CL2014000498A1 (en) 2011-08-29 2014-12-19 Infinity Pharmaceuticals Inc Heterocyclic compounds, selective inhibitors of class I pi3k isoforms; pharmaceutical composition that includes them; and method for treating a selected cancer disorder, an anti-inflammatory disease or an autoimmune disease.
DK2751109T3 (en) 2011-09-02 2017-01-23 Incyte Holdings Corp HETEROCYCLYLAMINES AS PI3K INHIBITORS
US9518217B2 (en) 2011-09-06 2016-12-13 E Ink Holdings Inc. Transition metal carbene complexes and the electroluminescent application thereof
WO2013040276A1 (en) 2011-09-13 2013-03-21 California Institute Of Technology Multi-metallic organometallic complexes, and related polymers, compositions, methods and systems
WO2013042137A1 (en) 2011-09-19 2013-03-28 Aurigene Discovery Technologies Limited Bicyclic heterocycles as irak4 inhibitors
US20140200347A1 (en) 2011-09-20 2014-07-17 Dow Corning Corporation Rhenium Containing Hydrosilylation Catalysts and Compositions Containing the Catalysts
US20140228570A1 (en) 2011-09-20 2014-08-14 Dow Corning Corporation Hydrosilylation Catalysts Made With Terdentate Nitrogen Ligands And Compositions Containing The Catalysts
WO2013043765A2 (en) 2011-09-20 2013-03-28 Dow Corning Corporation Hafnium containing hydrosilylation catalysts and compositions containing the catalysts
US20140249311A1 (en) 2011-09-20 2014-09-04 Dow Corning Corporation Iron Containing Hydrosilylation Catalysts and Compositions Containing the Catalysts
WO2013043799A1 (en) 2011-09-20 2013-03-28 Dow Corning Corporation Zirconium containing hydrosilylation catalysts and compositions containing the catalysts
WO2013043764A2 (en) 2011-09-20 2013-03-28 Dow Corning Corporation Silver containing hydrosilylation catalysts and compositions containing the catalysts
US20140182483A1 (en) 2011-09-20 2014-07-03 Dow Corning Corporation Titanium Containing Hydrosilylation Catalysts And Compositions Containing The Catalysts
EP2758410A2 (en) 2011-09-20 2014-07-30 Dow Corning Corporation Vanadium containing hydrosilylation catalysts and compositions containing the catalysts
US20140200349A1 (en) 2011-09-20 2014-07-17 Dow Corning Corporation Manganese Containing Hydrosilylation Catalysts and Compositions Containing the Catalysts
US9035053B2 (en) 2011-09-30 2015-05-19 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US9006444B2 (en) 2011-10-05 2015-04-14 Merck Sharp & Dohme Corp. Phenyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors
KR102083691B1 (en) 2011-10-14 2020-03-02 호도가야 가가쿠 고교 가부시키가이샤 New benzotriazole derivative and organic electroluminescent element in which said derivative is used
SG11201401587QA (en) 2011-10-17 2014-07-30 Univ Johns Hopkins Meldrum 's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors
WO2013063204A1 (en) 2011-10-26 2013-05-02 Kempharm, Inc. Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydromorphone, prodrugs, methods of making and use thereof
PL2770997T3 (en) 2011-10-28 2017-05-31 Vanderbilt University Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m1
CN103087050A (en) 2011-10-28 2013-05-08 山东轩竹医药科技有限公司 Aryl kinase inhibitor
KR20140090133A (en) 2011-11-07 2014-07-16 이데미쓰 고산 가부시키가이샤 Material for organic electroluminescent elements, and organic electroluminescent element using same
US8841450B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8841337B2 (en) 2011-11-09 2014-09-23 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
WO2013071094A1 (en) 2011-11-09 2013-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of atr kinase
US8846917B2 (en) 2011-11-09 2014-09-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9133131B2 (en) 2011-11-15 2015-09-15 Purdue Pharma L.P. Pyrimidine diol amides as sodium channel blockers
IN2014CN03469A (en) 2011-11-21 2015-07-03 Basf Se
JP2013129653A (en) 2011-11-22 2013-07-04 Nissan Chem Ind Ltd Triazole derivative and pest control agent
JP2013129651A (en) 2011-11-22 2013-07-04 Nissan Chem Ind Ltd Thiazole derivative and pest control agent
EA029473B1 (en) 2011-12-15 2018-03-30 Новартис Аг Use of pi3k inhibitors for treating acute and cerebral malaria
JP6058023B2 (en) 2011-12-15 2017-01-11 ファイザー・リミテッドＰｆｉｚｅｒ Ｌｉｍｉｔｅｄ Sulfonamide derivatives
CN103159738B (en) 2011-12-19 2016-09-07 上海泓博智源医药股份有限公司 The heteroaryl aroma compounds of alkynyl bridging and application thereof
US8969325B2 (en) 2011-12-19 2015-03-03 Abbvie Inc. TRPV1 antagonists
US8859584B2 (en) 2011-12-19 2014-10-14 Abbvie, Inc. TRPV1 antagonists
WO2013092936A2 (en) 2011-12-20 2013-06-27 Galderma Research & Development Use of 5-aminolevulinic acid and esters, in combination with a vitamin d derivative or analog in photochemotherapy, and their uses in treating acne
JP2014015447A (en) 2011-12-22 2014-01-30 Nissan Chem Ind Ltd Pyrazole derivative and pest control agent
US20130190356A1 (en) 2011-12-22 2013-07-25 Genentech, Inc. Benzyl sulfonamide derivatives as rorc modulators
WO2013099867A1 (en) 2011-12-27 2013-07-04 コニカミノルタ株式会社 Transparent electrode, electronic device, organic electroluminescence element, and method for manufacturing organic electroluminescence elements
US20150291514A1 (en) 2012-01-04 2015-10-15 Pfizer Limted N-Aminosulfonyl Benzamides
IN2012DE00110A (en) 2012-01-11 2015-05-08 Syngenta Ltd
AU2013216006B2 (en) 2012-01-31 2017-06-08 Daiichi Sankyo Company, Limited Pyridone derivatives
WO2013117649A1 (en) 2012-02-10 2013-08-15 Galapagos Nv Imidazo [4, 5 -c] pyridine derivatives useful for the treatment of degenerative and inflammatory diseases
US9138492B2 (en) 2012-02-23 2015-09-22 Canon Kabushiki Kaisha Particle containing hydrophobic dye having cyanine structure, and contrast agent containing the particle
US9340549B2 (en) 2012-03-05 2016-05-17 Amgen Inc. Oxazolidinone compounds and derivatives thereof
EP2830625A1 (en) 2012-03-28 2015-02-04 Merck Sharp & Dohme Corporation Insulin-like growth factor-1 receptor inhibitors
FR2988722B1 (en) 2012-04-03 2014-05-09 Sanofi Sa NOVEL THIENOPYRIMIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR THERAPEUTIC USES
DE102012006896A1 (en) 2012-04-05 2013-10-10 Merck Patent Gmbh New perfluoroalkyl fluorosilicate salts useful e.g. as solvent or solvent additive, catalyst or phase transfer catalyst, electrolyte component, fluorosurfactant, heat carrier, release agent or extracting agent, plasticizer, and lubricant
US8940742B2 (en) * 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN104245714B (en) 2012-04-12 2017-09-26 港大科桥有限公司 Platinum (II) complex compound applied for OLED
WO2013162061A1 (en) 2012-04-26 2013-10-31 第一三共株式会社 Bicyclic pyrimidine compound
WO2013161929A1 (en) 2012-04-26 2013-10-31 塩野義製薬株式会社 Pyridinyl morpholinone derivative and drug composition containing same
KR101383239B1 (en) 2012-04-30 2014-04-10 한국화학연구원 4-(Benzimidazol-2-ylamino)pyrrolidine derivatives inhibiting beta-secretase's activity and pharmaceutical composition containing the same as an active ingredient
AU2013255437A1 (en) 2012-05-02 2014-11-13 Lupin Limited Substituted pyridine compounds as CRAC modulators
JP2014001205A (en) 2012-05-22 2014-01-09 Nissan Chem Ind Ltd Parasiticide for animals
GB201209670D0 (en) 2012-05-31 2012-07-18 Convergence Pharmaceuticals Novel compounds
WO2013184794A2 (en) 2012-06-05 2013-12-12 Cara Therapeutics, Inc. Peripheral kappa receptor agonists for reducing pain and inflammation
EP2676947A1 (en) 2012-06-18 2013-12-25 LANXESS Deutschland GmbH Method for the isomerisation of substituted aromatic substances using a metal salt bath
CN103524372B (en) 2012-07-03 2015-06-10 南京圣和药业股份有限公司 Novel histone deacetylase inhibitor
JP2014111559A (en) 2012-07-04 2014-06-19 Nissan Chem Ind Ltd Pyrazole derivative and pest controlling agent
WO2014007395A1 (en) 2012-07-06 2014-01-09 日産化学工業株式会社 Pyrazole or thiazole derivative, salt thereof, and pest control agent
JP2015003895A (en) 2012-07-06 2015-01-08 日産化学工業株式会社 Thiazole derivative and pest control agent
WO2014011768A1 (en) 2012-07-10 2014-01-16 Adispell, Inc. Anti-anxiety treatment
WO2014018741A1 (en) 2012-07-27 2014-01-30 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
CN104703985A (en) 2012-08-09 2015-06-10 神经孔疗法股份有限公司 Aryl-and heteroaryl-substituted benzene derivatives as modulators of pi3-kinase signalling pathways
JP2014037382A (en) 2012-08-17 2014-02-27 Nissan Chem Ind Ltd Insecticidal, miticide, nematicide, molluscicide, germicide and bactericide composition, and method of controlling pest
WO2014033631A1 (en) 2012-08-31 2014-03-06 Novartis Ag N-(3-pyridyl) biarylamides as kinase inhibitors
ES2889757T3 (en) 2012-09-06 2022-01-13 Plexxikon Inc Compounds and methods for the modulation of kinases and indications for these
CN103664878A (en) 2012-09-12 2014-03-26 山东亨利医药科技有限责任公司 Hetero-aromatic ring and derivative type tyrosine kinase inhibitor thereof
KR102281288B1 (en) 2012-09-26 2021-07-26 에프. 호프만-라 로슈 아게 Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use
JP5994551B2 (en) 2012-10-10 2016-09-21 コニカミノルタ株式会社 Electroluminescence device
JP6127436B2 (en) 2012-10-10 2017-05-17 コニカミノルタ株式会社 White electroluminescent device and method of manufacturing white electroluminescent device
TWI598325B (en) 2012-10-12 2017-09-11 Ｈ 朗德貝克公司 Benzamides
JP6231009B2 (en) 2012-10-22 2017-11-15 コニカミノルタ株式会社 Transparent electrode, electronic device, and organic electroluminescence element
JP6015765B2 (en) 2012-10-22 2016-10-26 コニカミノルタ株式会社 Transparent electrode, electronic device, and organic electroluminescence element
WO2014065209A1 (en) 2012-10-23 2014-05-01 日本曹達株式会社 Pyridine compound or salt thereof, pest control agent, insecticide or acaricide, and ectoparasite control agent
KR102000211B1 (en) 2012-10-29 2019-09-30 삼성디스플레이 주식회사 Organometallic compound and organic light emitting diode comprising the same
NO2944633T3 (en) 2012-11-14 2018-06-30
US20140148484A1 (en) 2012-11-23 2014-05-29 Boehringer Ingelheim International Gmbh Pyrazole compounds for treating hairloss
CN104245693B (en) 2012-12-14 2016-08-24 上海恒瑞医药有限公司 Pyridine derivatives and officinal salt thereof, its preparation method and in application pharmaceutically
EP2935256B1 (en) 2012-12-19 2018-01-24 Bristol-Myers Squibb Company 4,6-diarylaminothiazines as bace1 inhibitors and their use for the reduction of beta-amyloid production
EP2934518B1 (en) 2012-12-19 2020-02-19 Merck Sharp & Dohme Corp. Spirocyclic cetp inhibitors
US9376408B2 (en) 2012-12-20 2016-06-28 Merck Sharp & Dohme Corp. Therapeutic thiazolidinone compounds
KR20140083620A (en) 2012-12-26 2014-07-04 제일모직주식회사 Photosensitive resin composition for light blocking layer and light blocking layer using the same
JP5911419B2 (en) 2012-12-27 2016-04-27 キヤノン株式会社 Organic light emitting device and display device
CN103896946B (en) 2012-12-28 2018-04-03 浙江导明医药科技有限公司 For preventing and treating the noval chemical compound of various autoimmune disease
WO2013171729A2 (en) 2013-01-08 2013-11-21 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl amide compounds as rorgamat modulator
TW201443037A (en) 2013-01-09 2014-11-16 Gilead Sciences Inc Therapeutic compounds
CN103694236B (en) 2013-01-15 2017-05-31 苏州开拓药业股份有限公司 A kind of pyrimidine scaffold has the antitumoral compounds of activity of hedgehog path antagonist
SG10201912524QA (en) 2013-01-15 2020-04-29 Incyte Holdings Corp Thiazolecarboxamides and pyridinecarboxamide compounds useful as pim kinase inhibitors
EP2952510B1 (en) 2013-02-02 2018-12-26 Chia Tai Tianqing Pharmaceutical Group Co.,Ltd Substituted 2-aminopyridine protein kinase inhibitor
US9840471B2 (en) 2013-02-19 2017-12-12 Senomyx, Inc. Compounds useful as modulators of TRPM8
PL2958921T3 (en) 2013-02-22 2018-01-31 Pfizer Pyrrolo [2, 3 -d]pyrimidine derivatives as inhibitors of janus kinases (jak)
CN103923085B (en) 2013-02-25 2016-08-24 苏州云轩医药科技有限公司 Pyridine-heterocyclic compound with activity of hedgehog path antagonist and application thereof
TW202214254A (en) 2013-03-01 2022-04-16 美商英塞特控股公司 USE OF PYRAZOLOPYRIMIDINE DERIVATIVES FOR THE TREATMENT OF PI3Kδ RELATED DISORDERS
EP2774919A1 (en) 2013-03-06 2014-09-10 Pharmeste S.R.L. In Liquidazione Novel sulfonamide TRPA1 receptor antagonists
JP2014198841A (en) 2013-03-12 2014-10-23 花王株式会社 Oxidizing composition
JP6279358B2 (en) 2013-03-12 2018-02-14 花王株式会社 Oxidizing composition
US8993771B2 (en) 2013-03-12 2015-03-31 Novira Therapeutics, Inc. Hepatitis B antiviral agents
JP6362367B2 (en) 2013-03-12 2018-07-25 花王株式会社 Oxidizing composition
JP2016512514A (en) 2013-03-13 2016-04-28 ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン Compositions containing thienopyrimidine and thienopyridine compounds and methods for their use
WO2014160185A2 (en) 2013-03-14 2014-10-02 The Board Of Trustees Of The Leland Stanford Junior University Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof
US9346802B2 (en) 2013-03-15 2016-05-24 Epizyme, Inc. CARM1 inhibitors and uses thereof
EP3401314B1 (en) 2013-03-15 2023-11-08 Araxes Pharma LLC Covalent inhibitors of kras g12c
SG11201507615SA (en) 2013-03-20 2015-10-29 Bayer Pharma AG 3-acetylamino-1-(phenyl-heteroaryl-aminocarbonyl or phenyl-heteroaryl-carbonylamino)benzene derivatives for the treatment of hyperproliferative disorders
KR101599009B1 (en) 2013-03-29 2016-03-14 동아에스티 주식회사 Novel oxazolidinone derivative as cetp inhibitors, its preparation method, and pharmaceutical composition comprising the same
AR096022A1 (en) 2013-04-11 2015-12-02 Basf Se SUBSTITUTED PYRIMIDINUM COMPOUNDS, USEFUL TO COMBAT ANIMAL PESTS
CN103193702B (en) 2013-04-18 2014-12-24 陕西师范大学 Functionalization method for nitrogenous heterocyclic compound
ITMI20130647A1 (en) 2013-04-19 2014-10-20 Univ Bologna Alma Mater COMPOUNDS WITH INHABITING ACTIVITIES ON SIRTUINES
US9783550B2 (en) 2013-05-14 2017-10-10 The Board Of Regents Of The University Of Texas System Highly potent inhibitors of porcupine
BR112015027591A2 (en) 2013-05-17 2017-07-25 Basf Se processes for the preparation of an acid, chloride and sulfimine compound
JP6468186B2 (en) 2013-05-31 2019-02-13 コニカミノルタ株式会社 Transparent electrode, electronic device, and organic electroluminescence element
US9193736B2 (en) 2013-06-11 2015-11-24 Janssen Pharmaceutica, Nv PDE 10a inhibitors for the treatment of type II diabetes
JP6184830B2 (en) 2013-06-14 2017-08-23 花王株式会社 Bleach cleaning composition
ES2784489T3 (en) 2013-06-27 2020-09-28 Lg Chemical Ltd Biaryl derivatives as GPR120 agonists
WO2015004029A1 (en) 2013-07-08 2015-01-15 Technische Universität München 18f-labeling of aromatic and heteroaromatic molecules with unprotected carboxylic acid groups
WO2015014900A1 (en) 2013-07-31 2015-02-05 Minoryx Therapeutics S.L. Di(hetero)arylamides and sulfonamides, methods for their preparation and therapeutic uses thereof
JPWO2015015993A1 (en) 2013-08-01 2017-03-02 コニカミノルタ株式会社 Organic electroluminescence device
US20160193202A1 (en) 2013-08-12 2016-07-07 Adispell, Inc. Therapeutic treatment for drug poisoning and addiction
WO2015025172A1 (en) 2013-08-22 2015-02-26 Mark David Charles 5-aryl-thiazol-2-yl-amine compounds and their therapeutic use
WO2015025962A1 (en) 2013-08-23 2015-02-26 富山化学工業株式会社 Amidine compound or salt thereof
US9359330B2 (en) 2013-08-26 2016-06-07 Purdue Pharma L.P. Substituted piperidines as sodium channel blockers
WO2015031561A1 (en) 2013-08-30 2015-03-05 Bp Corporation North America Inc. Catalytic conversion of alcohols
DE102013016324A1 (en) 2013-10-04 2015-04-09 Merck Patent Gmbh Perfluoroalkylfluoro- or Perfluoralkylchlorgermanate
TWI625164B (en) 2013-10-04 2018-06-01 中央研究院 Molecular catalysts capable of catalyzing oxidation of hydrocarbons and method for oxidizing hydrocarbons
CU24425B1 (en) 2013-11-01 2019-06-04 Novartis Ag AMINO-HETEROARIL-BENZAMIDAS AS CINASA INHIBITORS
WO2015066697A1 (en) 2013-11-04 2015-05-07 Forum Pharmaceuticals Inc. Fused morpholinopyrimidines and methods of use thereof
US10033000B2 (en) 2013-11-15 2018-07-24 Universal Display Corporation Organic electroluminescent materials and devices
US9340504B2 (en) 2013-11-21 2016-05-17 Purdue Pharma L.P. Pyridine and piperidine derivatives as novel sodium channel blockers
US9708278B2 (en) 2013-11-27 2017-07-18 Vanderbilt University Substituted 4-benzyl-3,4-dihydro-2H-benzo[B][1,4]oxazine-2-carboxamide analogs as positive allosteric modulators of muscarinic acetycholine receptor M1
MX2016007128A (en) 2013-12-02 2016-08-11 Chemocentryx Inc Ccr6 compounds.
US10355227B2 (en) 2013-12-16 2019-07-16 Universal Display Corporation Metal complex for phosphorescent OLED
GB201322334D0 (en) 2013-12-17 2014-01-29 Agency Science Tech & Res Maleimide derivatives as modulators of WNT pathway
WO2015089809A1 (en) 2013-12-19 2015-06-25 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
US9682960B2 (en) 2013-12-19 2017-06-20 Endorecherche, Inc. Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety
PL3082805T3 (en) 2013-12-20 2020-09-21 Institute For Drug Discovery, Llc Substituted amino triazoles, and methods using same
MA39145B1 (en) 2013-12-20 2018-05-31 Esteve Labor Dr Piperazine derivatives having multimode activity against pain
JP6340788B2 (en) 2013-12-25 2018-06-13 コニカミノルタ株式会社 Transparent electrode and electronic device
JP2015125845A (en) 2013-12-26 2015-07-06 コニカミノルタ株式会社 Transparent electrode and electronic device
KR20160106627A (en) 2013-12-30 2016-09-12 라이프에스씨아이 파마슈티컬스, 인크. Therapeutic inhibitory compounds
WO2015109109A1 (en) 2014-01-15 2015-07-23 Forum Pharmaceuticals Inc. Fused morpholinopyrimidines and methods of use thereof
US10093646B2 (en) 2014-01-17 2018-10-09 Novartis Ag 1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of SHP2
CN103848838A (en) 2014-01-23 2014-06-11 中国药科大学 c-Met-VEGFR-2 double antagonist, preparation method and medical use thereof
JP2015141806A (en) 2014-01-28 2015-08-03 出光興産株式会社 Method for manufacturing organic electroluminescent element, composition, organic electroluminescent element, and electronic device
CN103804312B (en) 2014-02-17 2016-04-20 四川百利药业有限责任公司 Aza cyclic cpds and its production and use
US9673407B2 (en) 2014-02-28 2017-06-06 Universal Display Corporation Organic electroluminescent materials and devices
US9775839B2 (en) 2014-03-13 2017-10-03 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
RU2016137674A (en) 2014-03-17 2018-04-18 Ф. Хоффманн-Ля Рош Аг Piperidinedione derivatives
WO2015142903A2 (en) 2014-03-17 2015-09-24 Genentech, Inc. Method of controlling lactate production with piperdine-dione derivatives
WO2015139621A1 (en) 2014-03-18 2015-09-24 北京韩美药品有限公司 4-heteroaryl substituted benzoic acid or benzamides compound
CN110483335B (en) 2014-03-19 2023-08-11 阿米达斯公司 Amyloid targeting agents and methods of use thereof
CN104926801B (en) 2014-03-22 2019-06-04 浙江大学 Substituted azetidine analog derivative, the pharmaceutical composition containing it and its application in antitumor
JP6269260B2 (en) 2014-03-31 2018-01-31 宇部興産株式会社 Method for producing biaryl compound
EP2933849A1 (en) 2014-04-15 2015-10-21 cynora GmbH Host materials for OLEDs
WO2015160636A1 (en) 2014-04-16 2015-10-22 Merck Sharp & Dohme Corp. Factor ixa inhibitors
CA2945212A1 (en) * 2014-04-24 2015-10-29 Novartis Ag Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors
CN106458966B (en) * 2014-04-24 2019-05-07 诺华股份有限公司 Pyrazines derivatives as inhibitors of phosphatidylinositol3 3-kinase
CN106456836B (en) 2014-04-29 2019-12-06 微仙美国有限公司 Polymers comprising active agents
US9981972B2 (en) 2014-05-22 2018-05-29 Abide Therapeutics, Inc. N-hydroxy bicyclic hydantoin carbamates as tools for identification of serine hydrolase targets
CN105461738B (en) 2014-06-03 2019-03-08 中国人民解放军军事医学科学院毒物药物研究所 A kind of rapamycin derivative, preparation method, its pharmaceutical composition and purposes
CN104004026A (en) 2014-06-09 2014-08-27 江西冠能光电材料有限公司 Electronegative phosphor material
RS59054B1 (en) 2014-06-17 2019-08-30 Vertex Pharma Method for treating cancer using a combination of chk1 and atr inhibitors
CN106573931A (en) 2014-06-18 2017-04-19 拜耳医药股份有限公司 Bet-protein inhibiting 3,4-dihydropyrido[2,3-b]pyrazinones with meta-substituted aromatic amino- or ether groups
GB201411239D0 (en) 2014-06-25 2014-08-06 Takeda Pharmaceutical Novel compounds
GB201411236D0 (en) 2014-06-25 2014-08-06 Takeda Pharmaceutical Novel compounds
JP6204591B2 (en) 2014-07-07 2017-09-27 富士フイルム株式会社 Photoelectric conversion element, dye-sensitized solar cell, metal complex dye, dye solution, and terpyridine compound or esterified product thereof
CN106463273B (en) 2014-07-07 2019-01-15 富士胶片株式会社 Photo-electric conversion element, dye-sensitized solar cell, metal complex dye, pigment solution and terpyridyl compounds or its carboxylate
CN105315199B (en) 2014-07-14 2020-11-20 湖南化工研究院有限公司 N-pyridine aryloxy phenoxy carboxylic acid derivative and preparation method and application thereof
BR112017000764B1 (en) 2014-07-14 2022-07-12 Shanghai Jia Tan Pharmatech Co. Ltd. COMPOUND, METHOD FOR PREPARING COMPOUND AND USE OF COMPOUND
SG11201700039TA (en) 2014-07-23 2017-02-27 Aurigene Discovery Tech Ltd 4,5-dihydroisoxazole derivatives as nampt inhibitors
CA2955919A1 (en) 2014-07-25 2016-01-28 Piramal Enterprises Limited Substituted phenyl alkanoic acid compounds as gpr120 agonists and uses thereof
SG10201901010PA (en) 2014-08-05 2019-03-28 Alios Biopharma Inc Combination therapy for treating a paramyxovirus
JO3589B1 (en) 2014-08-06 2020-07-05 Novartis Ag Protein kinase c inhibitors and methods of their use
KR101887213B1 (en) 2014-08-12 2018-08-09 삼성에스디아이 주식회사 Compound, organic optoelectric device and display device
EP3183255B1 (en) 2014-08-18 2023-07-05 Hudson Biopharma Inc. Spiropyrrolidines as mdm2 inhibitors
US20170290806A1 (en) 2014-09-08 2017-10-12 Temple University-Of The Commonwealth System Of Higher Education PCSK9 Inhibitors and Methods of Use Thereof
US10669635B2 (en) 2014-09-18 2020-06-02 Baker Hughes, A Ge Company, Llc Methods of coating substrates with composite coatings of diamond nanoparticles and metal
WO2016049565A1 (en) 2014-09-25 2016-03-31 Araxes Pharma Llc Compositions and methods for inhibition of ras
WO2016049524A1 (en) 2014-09-25 2016-03-31 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
JP6100745B2 (en) 2014-10-01 2017-03-22 ユー・ディー・シー アイルランド リミテッド Organic electroluminescence device
EP3201187A4 (en) 2014-10-01 2018-04-11 The Brigham and Women's Hospital, Inc. Compositions and methods for inhibiting bmp
DK3204381T3 (en) 2014-10-08 2022-07-25 Redx Pharma Plc N-PYRIDINYLACETAMID DERIVATIVES AS WNT SIGNALING PATHWAY INHIBITORS
HUE046914T2 (en) 2014-10-08 2020-04-28 Redx Pharma Plc N-pyridinyl acetamide derivatives as inhibitors of the wnt signalling pathway
US10759791B2 (en) 2014-11-04 2020-09-01 Northwestern University Mammalian and bacterial nitric oxide synthase inhibitors
US9951014B2 (en) 2014-11-04 2018-04-24 Northwestern University Mammalian and bacterial nitric oxide synthase inhibitors
WO2016073470A1 (en) 2014-11-04 2016-05-12 The University Of Kansas Lkb1-ampk activators for therapeutic use in polycystic kidney disease
WO2016074757A1 (en) 2014-11-11 2016-05-19 Merck Patent Gmbh Method for the preparation of mono- and bis(perfluoroalkyl)fluorophosphate salts and their acids
WO2016088354A1 (en) 2014-12-05 2016-06-09 出光興産株式会社 Metal complex compound, material for organic electroluminescent element, composition, organic electroluminescent element, and electronic device
CN104557863B (en) 2014-12-18 2017-03-15 中国科学院广州生物医药与健康研究院 A kind of new Nampt inhibitor and its synthetic method and application
JP6621477B2 (en) 2014-12-18 2019-12-18 ファイザー・インク Pyrimidine and triazine derivatives and their use as AXL inhibitors
EP3237407B1 (en) 2014-12-23 2020-04-15 SMA Therapeutics, Inc. 3,5-diaminopyrazole kinase inhibitors
JP6502091B2 (en) 2014-12-26 2019-04-17 国立研究開発法人産業技術総合研究所 High pressure hydrogen production method and production system
EP3247771B1 (en) 2015-01-20 2020-06-10 Cynora Gmbh Pyridines and derivatives thereof as components for use in optoelectronic components
CN105845831B (en) 2015-01-30 2019-07-05 三星显示有限公司 Organic light emitting apparatus
CN107207958B (en) 2015-02-03 2018-11-16 住友化学株式会社 Composition and the light-emitting component for using the composition
WO2016130501A1 (en) 2015-02-09 2016-08-18 Incyte Corporation Aza-heteroaryl compounds as pi3k-gamma inhibitors
CN104744348B (en) 2015-02-13 2018-01-09 华侨大学 Polysubstituted pyridine derivative and preparation method thereof
US9701671B2 (en) 2015-02-20 2017-07-11 Canon Kabushiki Kaisha Organic compound, electrochromic element containing the same, optical filter, lens unit, imaging device, and window component
RS63963B1 (en) 2015-02-27 2023-03-31 Incyte Holdings Corp Processes for the preparation of a pi3k inhibitor
WO2016140973A1 (en) 2015-03-02 2016-09-09 Sanford-Burnham Medical Research Institute Quinolinones as inhibitors of translation initiation complex
ES2872553T3 (en) 2015-03-06 2021-11-02 Pharmakea Inc Lysyl oxidase type-2 inhibitors and uses thereof
WO2016161145A1 (en) 2015-03-31 2016-10-06 Dana-Farber Cancer Institute, Inc. Stk4 inhibitors for treatment of hematologic malignancies
US11021468B2 (en) 2015-04-01 2021-06-01 Rigel Pharmaceuticals, Inc. TGF-ß inhibitors
EA035406B1 (en) 2015-04-08 2020-06-09 Торрент Фармасьютикалз Лимитед Pyridinium compounds
KR101953175B1 (en) 2015-04-24 2019-02-28 주식회사 엘지화학 Multicyclic compound including nitrogen and organic light emitting device using the same
WO2016173557A1 (en) 2015-04-30 2016-11-03 中国科学院上海药物研究所 Compound having kinase inhibition activity, and preparation method and uses
CA2984183C (en) 2015-05-01 2021-11-09 Pfizer Inc. Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl, pyrrolo[2,3-b]pyridinyl acrylamides and epoxides thereof
GB201507753D0 (en) 2015-05-06 2015-06-17 Biolipox Ab New compounds and uses
JP7083247B2 (en) 2015-05-08 2022-06-10 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Luminescent material, luminescent thin film, organic electroluminescence element, display device and lighting device
WO2016191245A1 (en) 2015-05-22 2016-12-01 Dow Agrosciences Llc Recovery and/or reuse of palladium catalyst after a suzuki coupling
US11925102B2 (en) 2015-06-04 2024-03-05 Universal Display Corporation Organic electroluminescent materials and devices
CN104927742B (en) 2015-06-23 2017-05-17 上海东和胶粘剂有限公司 Polyurethane wood structure glue and preparation method thereof
JP2017019789A (en) 2015-07-13 2017-01-26 大阪ガスケミカル株式会社 Microorganism controlling agent
WO2017011279A1 (en) 2015-07-13 2017-01-19 Merck Sharp & Dohme Corp. Bicyclic heterocycles as inhibitors of cholesterol ester transfer protein
CN105175202B (en) 2015-07-14 2018-09-07 绍兴文理学院 The method that biaryl is prepared by aryl hydrazine
TWI608132B (en) 2015-08-06 2017-12-11 羅門哈斯電子材料有限公司 Method of electroplating photoresist defined features from copper electroplating baths containing reaction products of pyridyl alkylamines and bisepoxides
KR101735687B1 (en) 2015-09-23 2017-05-15 롯데케미칼 주식회사 Catalyst system for olefin oligomerization, and method for olefin oligomerization using the same
KR101832448B1 (en) 2015-09-24 2018-02-26 롯데케미칼 주식회사 Catalyst system for olefin oligomerization, and method for olefin oligomerization using the same
US20170092880A1 (en) 2015-09-25 2017-03-30 Universal Display Corporation Organic electroluminescent materials and devices
WO2017058807A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2017058728A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
MX2018003657A (en) 2015-09-30 2018-04-30 Vertex Pharma Method for treating cancer using a combination of dna damaging agents and atr inhibitors.
WO2017059434A1 (en) 2015-10-02 2017-04-06 Esanex, Inc. Use of tetrahydroindazolylbenzamide and tetrahydroindolylbenzamide derivatives for the treatment of cancer
US9890149B2 (en) 2015-10-07 2018-02-13 NuBridge BioSciences Isothiazole derivatives as CFTR modulators
US9981945B2 (en) 2015-10-07 2018-05-29 NuBridge BioSciences Pyrimidine derivatives as CFTR modulators
US10174002B2 (en) 2015-10-07 2019-01-08 NuBridge BioSciences Pyridine derivatives as CFTR modulators
WO2017061581A1 (en) 2015-10-08 2017-04-13 株式会社神鋼環境ソリューション Method for synthesizing bipyridine compound and method for manufacturing pyridine compound
WO2017060406A1 (en) 2015-10-09 2017-04-13 Janssen Pharmaceutica Nv Quinoxaline and pyridopyrazine derivatives as pi3kbeta inhibitors
WO2017070003A1 (en) 2015-10-20 2017-04-27 Kiacta Sárl Use of prodrugs of 1,3-propanedisulfonic acid or pharmaceutically acceptable salts thereof for the treatment of sarcoidosis
US11033539B2 (en) 2015-11-06 2021-06-15 Neurocrine Biosciences, Inc. Compounds of formulas (VII), (VIII), (IX), (XI), (XII), (XIII), and (XIV) as muscarinic receptor 4(M4) antagonists for treating neurological diseases
WO2017087695A1 (en) 2015-11-17 2017-05-26 Taipei Medical University Aminonaphthoquinone compounds for treatment and/or prevention of fibrosis diseases
EP3388428B1 (en) 2015-12-07 2021-08-04 Suzhou Sinovent Pharmaceuticals Company Five-membered heterocyclic amides wnt pathway inhibitor
WO2017100644A1 (en) 2015-12-09 2017-06-15 Case Western Reserve University Method of modulating ribonucleotide reductase
TWI773657B (en) 2015-12-18 2022-08-11 美商亞德利克斯公司 Substituted 4-phenyl pyridine compounds as non-systemic tgr5 agonists
KR102396293B1 (en) 2015-12-29 2022-05-11 삼성디스플레이 주식회사 Organic light-emitting device
KR102419178B1 (en) 2015-12-29 2022-07-11 삼성디스플레이 주식회사 Organic light-emitting device
ES2833955T3 (en) 2016-01-05 2021-06-16 Incyte Corp Pyridines substituted with pyrazole / imidazole as PI3K-Gamma inhibitors
US20190008856A1 (en) 2016-01-08 2019-01-10 The Institute Of Cancer Research: Royal Cancer Hospital Inhibitors of ataxia-telangiectasia mutated and rad3-related protein kinase (atr) for use in methods of treating cancer
WO2017127637A1 (en) 2016-01-22 2017-07-27 Chevron Oronite Company Llc Synergistic lubricating oil composition containing a mixture of olefin copolymer dispersant-type viscosity improver and amine compound
US10964902B2 (en) 2016-01-28 2021-03-30 Sumitomo Chemical Company, Limited Film production method
KR20170093273A (en) 2016-02-03 2017-08-16 주식회사 동진쎄미켐 organic light emitting device
WO2017170765A1 (en) 2016-03-30 2017-10-05 田辺三菱製薬株式会社 Novel nitrogen-containing heterocyclic compound
US10236456B2 (en) 2016-04-11 2019-03-19 Universal Display Corporation Organic electroluminescent materials and devices
AU2017254711B2 (en) 2016-04-22 2021-01-21 Dana-Farber Cancer Institute, Inc. Degradation of cyclin-dependent kinase 8 (CDK8) by conjugation of CDK8 inhibitors with E3 ligase ligand and methods of use
WO2017189569A1 (en) 2016-04-25 2017-11-02 Trustees Of Tufts College Multimediator dpp4 and fap inhibitors, and uses related thereto
US20170305861A1 (en) 2016-04-25 2017-10-26 Immunomet Therapeutics, Inc Heteroaryl compounds comprising nitrogen and use thereof
US20170320875A1 (en) 2016-05-06 2017-11-09 Incyte Corporation Heterocyclic compounds as immunomodulators
EP3455218A4 (en) 2016-05-10 2019-12-18 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
AR108875A1 (en) 2016-06-24 2018-10-03 Incyte Corp HETEROCYCLIC COMPOUNDS AS PI3K-g INHIBITORS
CA3029857C (en) 2016-07-05 2023-07-04 Guangzhou Maxinovel Pharmaceuticals Co., Ltd Aromatic acetylene or aromatic ethylene compound, intermediate, preparation method, pharmaceutical composition and use thereof
CN107759614B (en) 2016-08-16 2023-01-24 中国科学院上海药物研究所 Oxazolopyridine quaternary ammonium salt compound, preparation method and application thereof
CN109863142B (en) 2016-08-24 2022-06-10 豪夫迈·罗氏有限公司 2-azabicyclo [3.1.0] hex-3-one derivatives and methods of use
EP3507289B1 (en) 2016-09-02 2020-07-15 Suven Life Sciences Limited Muscarinic m1 receptor positive allosteric modulators
US10981154B2 (en) 2016-09-21 2021-04-20 Lotte Chemical Corporation Catalyst system for olefin oligomerization and method for preparing olefin oligomer using same
WO2018056644A1 (en) 2016-09-21 2018-03-29 롯데케미칼 주식회사 Catalyst system for olefin oligomerization and method for preparing olefin oligomer using same
US10160724B2 (en) 2016-09-28 2018-12-25 Dong-A St Co., Ltd. Tetrahydropyridine derivatives and their use as antibacterial agents
TWI734861B (en) 2016-12-19 2021-08-01 瑞典商指紋卡公司 Capacitive fingerprint sensing device comprising display functionality
CN106831735B (en) 2017-01-23 2019-10-11 牡丹江医学院 A kind of heterocyclic compound and its preparation method and application for treating osteoporosis
CN106905299B (en) 2017-02-28 2019-04-02 牡丹江医学院 A kind of drug and preparation method thereof for treating pancreatitis
BR112020007593A2 (en) * 2017-10-18 2020-09-24 Incyte Corporation condensed imidazole derivatives replaced by tertiary hydroxy groups as pi3k-gamma inhibitors
IL277071B2 (en) 2018-03-08 2024-07-01 Incyte Corp AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS
WO2020010003A1 (en) 2018-07-02 2020-01-09 Incyte Corporation AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS

Also Published As

Publication number Publication date
KR20200142508A (en) 2020-12-22
HRP20220331T1 (en) 2022-05-13
CN112074505A (en) 2020-12-11
JP2023099049A (en) 2023-07-11
MD3762368T2 (en) 2022-07-31
DK3762368T3 (en) 2022-03-28
UA128288C2 (en) 2024-05-29
IL277071A (en) 2020-10-29
IL302529A (en) 2023-07-01
US11926616B2 (en) 2024-03-12
SI3762368T1 (en) 2022-06-30
US20200339542A1 (en) 2020-10-29
EP3762368B1 (en) 2022-01-26
US20190276435A1 (en) 2019-09-12
JP7558334B2 (en) 2024-09-30
PH12020551390A1 (en) 2021-11-22
MX2020009228A (en) 2021-01-08
US10669262B2 (en) 2020-06-02
US20220213065A1 (en) 2022-07-07
LT3762368T (en) 2022-06-10
WO2019226213A2 (en) 2019-11-28
IL302529B1 (en) 2024-11-01
RS63124B1 (en) 2022-05-31
JP2021515773A (en) 2021-06-24
EP4056560A1 (en) 2022-09-14
MX2023000100A (en) 2023-02-09
CA3093445A1 (en) 2019-11-28
WO2019226213A3 (en) 2020-01-02
TW202413336A (en) 2024-04-01
AU2019272342A1 (en) 2020-09-24
PL3762368T3 (en) 2022-06-06
BR112020018094A2 (en) 2020-12-22
SG11202008560VA (en) 2020-10-29
IL277071B2 (en) 2024-07-01
EP3762368A2 (en) 2021-01-13
CL2020002275A1 (en) 2021-02-19
TWI827583B (en) 2024-01-01
CY1125169T1 (en) 2024-02-16
TW201938542A (en) 2019-10-01
CN118290402A (en) 2024-07-05
PT3762368T (en) 2022-05-06
AU2024203916A1 (en) 2024-06-27
ECSP20061378A (en) 2021-04-29
PE20210641A1 (en) 2021-03-23
MA54133B1 (en) 2022-01-31
ES2910071T3 (en) 2022-05-11
CR20240101A (en) 2024-05-24
AU2019272342B2 (en) 2024-03-07
MA54133A (en) 2021-01-13
JP7268049B2 (en) 2023-05-02
CN112074505B (en) 2024-04-05
HUE057970T2 (en) 2022-06-28
CO2020012169A2 (en) 2020-12-21
CR20200464A (en) 2021-04-14

Similar Documents

Publication Publication Date Title
AU2019272342B2 (en) Aminopyrazine diol compounds as PI3K-y inhibitors
US11926630B2 (en) Tertiary alcohols as PI3K-γ inhibitors
US11161838B2 (en) Heterocyclic derivatives as PI3K inhibitors
US11046658B2 (en) Aminopyrazine derivatives as PI3K-γ inhibitors
EA045434B1 (en) AMINOPYRAZINDIOL COMPOUNDS AS PI3Kγ INHIBITORS
EA043981B1 (en) TERTIARY ALCOHOLS AS PI3K-γ INHIBITORS